
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)13407-X
10.1016/j.heliyon.2024.e37376
e37376
Review Article
Targeting autophagy can synergize the efficacy of immune checkpoint inhibitors against therapeutic resistance: New promising strategy to reinvigorate cancer therapy
Hashemi Mehrdad ab
Mohandesi Khosroshahi Elaheh a
Tanha Mahsa c
Khoushab Saloomeh a
Bizhanpour Anahita a
Azizi Farnaz a
Mohammadzadeh Mahsa ab
Matinahmadi Arash d
Khazaei Koohpar Zeinab e
Asadi Saba a
Taheri Hengameh a
Khorrami Ramin f
Ramezani Farani Marzieh g
Rashidi Mohsen dr.mohsenrashidi@yahoo.com
hi⁎⁎
Rezaei Mahdi dr.mrezaei98@gmail.com
j⁎⁎⁎
Fattah Eisa eesa.fat@gmail.com
k⁎⁎⁎⁎
Taheriazam Afshin a.taheriazam@iautmu.ac.ir
al⁎⁎⁎⁎⁎
Entezari Maliheh mentezari@iautmu.ac.ir
ab⁎
a Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
b Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
c Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, United States
d Department of Cellular and Molecular Biology, Nicolaus Copernicus University, Torun, Poland
e Department of Cell and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
f Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
g Department of Biological Sciences and Bioengineering, Nano Bio High-Tech Materials Research Center, Inha University, 100 Inha-ro, Michuhol-gu, Incheon, 22212, Republic of Korea
h Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
i The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
j Health Research Center, Chamran Hospital, Tehran, Iran
k School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
l Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
⁎ Corresponding author. Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. mentezari@iautmu.ac.ir
⁎⁎ Corresponding author. Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. dr.mohsenrashidi@yahoo.com
⁎⁎⁎ Corresponding author. dr.mrezaei98@gmail.com
⁎⁎⁎⁎ Corresponding author. eesa.fat@gmail.com
⁎⁎⁎⁎⁎ Corresponding author. Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. a.taheriazam@iautmu.ac.ir
03 9 2024
30 9 2024
03 9 2024
10 18 e373766 4 2024
29 6 2024
2 9 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Immune checkpoints are a set of inhibitory and stimulatory molecules/mechanisms that affect the activity of immune cells to maintain the existing balance between pro- and anti-inflammatory signaling pathways and avoid the progression of autoimmune disorders. Tumor cells can employ these checkpoints to evade immune system. The discovery and development of immune checkpoint inhibitors (ICIs) was thereby a milestone in the area of immuno-oncology. ICIs stimulate anti-tumor immune responses primarily by disrupting co-inhibitory signaling mechanisms and accelerate immune-mediated killing of tumor cells. Despite the beneficial effects of ICIs, they sometimes encounter some degrees of therapeutic resistance, and thereby do not effectively act against tumors. Among multiple combination therapies have been introduced to date, targeting autophagy, as a cellular degradative process to remove expired organelles and subcellular constituents, has represented with potential capacities to overcome ICI-related therapy resistance. It has experimentally been illuminated that autophagy induction blocks the immune checkpoint molecules when administered in conjugation with ICIs, suggesting that autophagy activation may restrict therapeutic challenges that ICIs have encountered with. However, the autophagy flux can also provoke the immune escape of tumors, which must be considered. Since the conventional FDA-approved ICIs have designed and developed to target programmed cell death receptor/ligand 1 (PD-1/PD-L1) as well as cytotoxic T lymphocyte-associated molecule 4 (CTLA-4) immune checkpoint molecules, we aim to review the effects of autophagy targeting in combination with anti-PD-1/PD-L1- and anti-CTLA-4-based ICIs on cancer therapeutic resistance and tumor immune evasion.

Graphical abstract

Image 1

Highlights

• Tumor cells can exploit immune checkpoint mechanisms to subvert the immune system.

• Immune checkpoint inhibitors block the immune evasion of tumors to decelerate cancer progression.

• A set of tumors indicate diverse degrees of resistance against immune checkpoint inhibitors.

• Targeting autophagy may enhance the efficacy of immune checkpoint-based therapeutics to overcome therapy resistance.

Keywords

Neoplasms
Immune checkpoint inhibitors
Autophagy
Tumor escape
Therapy resistance
==== Body
pmc1 Introduction

Despite multiple developments in cancer therapy, the expansion of therapeutic resistance is still a major obstacle in achieving long-term remedies [[1], [2], [3]]. In recent years, many researchers as well as oncologists have sought such novel approaches to overcome therapy resistance and boost the efficacy of conventional cancer treatments [[4], [5], [6], [7], [8], [9]]. A promising opened up avenue in this area of research involves the conjugation of two potential therapeutic strategies; i.e. targeting autophagy and utilizing ICIs, combined.

Autophagy is a cellular process that facilitates the degradation and restoration of damaged proteins and organelles, by which supporting the cellular homeostasis [[10], [11], [12], [13]]. Thereby, deregulation of the autophagy flux can result in the onset and progression of multiple cancers by deteriorating the therapy resistance and tumor growth [[14], [15], [16], [17], [18]]. On the other hand, ICIs have transfigured the process of cancer therapy by forcing the body's immune system to fight tumor cells [[19], [20], [21], [22]]. In depth, these inhibitors have the ability of blocking immune checkpoints, as particular molecules and mechanisms accounting for the suppression of immune responses, which in turn uncover the immune system's abilities to perceive and eradicate cancer cells [[23], [24], [25]]. PD-1/PD-L1 and CTLA-4 molecules and their related mechanisms are the best studied immune checkpoint pathways in maintaining standard immune activities that can be blocked by specific ICIs [[26], [27], [28], [29], [30]]. Although ICIs have represented considerable degrees of therapeutic success in a number of patients, a significant proportion still experience therapeutic failure [[31], [32], [33], [34]].

Understanding the intricate interplay between autophagy and immune checkpoint pathways can provide new horizons to combination therapies that hold promise in overcoming therapeutic resistance [35,36]. Mounting evidence suggests that targeting autophagy has the potential of sensitizing cancer cells to ICIs, leading to improvement of treatment outcomes and patient survival rates [37]. Preclinical studies have demonstrated that inhibition of autophagy synergized with immune checkpoint blockade boosts immune responses against tumors and promotes tumor cell death [38,39]. By disrupting autophagy, cancer cells become more vulnerable to immune-mediated killing, allowing ICIs to exert their full potential [40]. This observed synergy between autophagy targeting and immune checkpoint blockade offers a novel approach to counteract molecular mechanisms by which treatment resistance is developed, and also enhance the efficacy of approved immunotherapeutic interventions [41].

Clinical findings are limited in this field and ongoing clinical trials are investigating the safety and efficacy of autophagy-ICIs combination regimens in various cancer types. Still, the obtained results from preclinical evaluations are encouraging and highlight the potential of the above-stated therapeutic strategy to extend the benefits of ICIs to a broader spectrum of cancer-suffering patients and overcome therapy resistance [36,42].

The current review aims to highlight the complex crosstalk between autophagy and the immune system to pave the road for more effective and personalized treatment procedures. As ongoing analyses further clarify the concealed mechanisms and optimize the ordinary therapeutic strategies, the potential of revolutionizing cancer remission and improving patient survival is within reach.

2 Autophagy and therapeutic response

2.1 The autophagy machinery at a glance

Autophagy is a tightly regulated flux that is responsible for the degradation of defective organelles and aggregates of misfolded proteins, getting assistance from lysosomes [[43], [44], [45]]. Although the autophagy was first narrated in the 1960s, the recognition of autophagy-related genes (Atgs) was arisen in the 1990s, propelling significant innovations in elucidating the mechanistic convolutions of autophagy [10,46]. Autophagy initiates with the formation of a double-membrane vesicle, autophagosome that is originated from a phagophore, which is regulated by the mTOR (mammalian target of rapamycin) [[47], [48], [49], [50]]. Phagophore formation is further controlled by the activation of the PI3K, the class III phosphatidylinositol 3-kinase, a.k.a. vacuolar protein sorting 34 (Vps34) that is responsible for triggering the conversion of PI to PI3P. For developing the elongation of the autophagic membrane, the Vps34 targets the newly generated membranes through linking to Atg14, and the PI3P effector proteins are then recruited by PI3P into the phagophore sites [[51], [52], [53]]. The Atg12-Atg5 complex and light chain 3 (LC3) are necessary systems to control the membrane elongation. Atg12 is first activated by Atg7 to bind to Atg10 in order to be conjugated with Atg5. The newly formed Atg12-Atg5 complex connects to Atg16L, and thus the multimeric Atg12-Atg5-Atg16L is generated. In an Atg16L-dependent manner, the corresponding complex is transferred to the outer membrane of phagophore until the elongation is completed [[54], [55], [56]]. On the other hand, the cytosolic isoform of LC3, i.e. LC3-I, is conjugated to phosphatylethanolamine (PE) to be reconstructed into LC3-II, depending on the presence of Atg3 and Atg7. This LC3-II that is located in both inner and outer membranes of the phagophore, specifically controls the elongation step [57]. The expansion of phagophore eventually results in the formation of the autophagosome [58,59].

The autophagosome, containing detrimental organelles and macromolecules, will then be merged with a lysosome to from the autolysosome for further degradation mediated by lysosomal hydrolases [49]. The development of autophagosome-lysosome fusion is facilitated by lysosomal-associated membrane proteins 1 and 2 (LAMP-1 and LAMP-2) [60]. Although both LAMPs participate in the fusion step, LAMP-2 has been found to be the predominant protein in this context, as its deficiency causes more adverse effects [15,61]. Beyond these lysosomal associated proteins, Rab-7, as a small GTPase Ras-associated protein, also contributes to the maturation process [62,63]. Ultimately, the autophagosomal cargos are degraded and recycled to nutritionally support the cell (Fig. 1) [64]. It is worth noting that the autophagosomal degradation process is not on the basis of random choice, and is a selective removal process relying on the existence of p62/sequestosome-1 (SQSTM1) multi-adaptor molecule and the BAG3 co-chaperone [65,66].Fig. 1 Autophagy flux; from beginning to end. The initiation step of autophagy, i.e. phagophore formation, is provoked by the initiation complex ULK1/2- Atg13-FIP200-ATG101, which can be inhibited by mTOR. In the next step, Vps34 is activated and connects to Beclin1, Vps15, and Atg14 to conduct the nucleation process and further progression of the phagophore formation. The newly generated phagophores are elongated to form autophagosomes under the regulation of LC3-II and Atg12-Atg5-Atg16L complex. In the following, autophagosomes can fuse with either endosomes or lysosomes to degrade and remove subcellular debris, and thus provide an enriched cellular nutrient pool.

Fig. 1

2.2 Autophagy and cancer

Since autophagy-mediated recycling of defected organelles and macromolecules is highly conserved, it would undesirably affect genomic integrity and cellular homeostasis if becomes deregulated, thus being involved in the pathogenesis of a wide spectrum of disorders from neurodegenerative diseases to multiple cancers [15,[67], [68], [69]]. By serving as a quality control machinery through starvation as well as other subcellular stress circumstances, autophagy is involving in cell survival; thereby, once it is inhibited, detrimental ingredients are no longer removed, resulting in an oversensitivity against cell death progression. Furthermore, accumulating evidence has shown that uninterrupted activation of the autophagy flux can stimulate the autophagic cell death [65,70,71]. In the case of tumorigenesis and tumor development, autophagy has a dual role as it functions as a tumor suppressor at the commencement to support genomic integrity, while acts as an oncogenic flux in the later stages of tumor progression [72]. Thus, the beneficial or harmful effects of autophagy are context-dependent and indeed it is considered a double-edged sword in oncogenesis and cancer progression.

Autophagy can also provoke the expression of tumor suppressor genes/proteins or oncogenes/-proteins. Tumor suppressor contributors, which can be silenced by mTOR and AMP-activated protein kinase (AMPK), stimulate the autophagy and subsequent inhibition of tumorigenesis [[73], [74], [75]]. Whilst, oncogenes have been found to be switched on by mTOR, class I PI3K, and protein kinase B (Akt) to block autophagy and further progression of oncogenesis [76,77]. Literally, the mutation of key ATGs decelerates or even ceases the tumor development. It is exemplified by Bax-interacting factor 1 protein (BIF-1) that is mutated or abnormal in many cancer species [78,79]. Also, UV radiation resistance-associated protein (UVRAG), which is an autophagy modulator in relation to BECN1, can suppress autophagy in its mutated from, leading to a provoked cancer cell proliferation [80]. A huge number of Ras-associated malignancies have also been reported with high basal-level of autophagy [81]. Taken together, either suppression or activation of autophagy can be potential approaches to eradicate cancer (Fig. 2).Fig. 2 Dual role of autophagy in cancer. In a tumor cell, autophagy can be activated by tumor suppressor genes/proteins or be inhibited by oncogenes/onco-proteins. In this context, autophagy activation may desirably fight tumor cell, while the inhibited autophagy can result in tumor progression. mTOR and AMPK inhibit the corresponding tumor suppressors, and the same mTOR along with PI3K/Akt stimulate oncogenic factors.

Fig. 2

2.3 Mechanisms linking autophagy and therapeutic resistance

As a process of cellular self-degradation, autophagy has been found to play a complex role in cancer therapy resistance. Whilst autophagy can promote cell survival during stress conditions, it can also contribute to cell death under certain circumstances [82,83]. The interplay between autophagy and therapeutic resistance in cancer involves several mechanisms; for instance, autophagy can be activated in cancer cells as a survival mechanism in response to various stresses induced by cancer therapies, such as chemotherapy, radiation, or targeted therapies. In other words, it assists cancer cells remove damaged organelles and proteins, maintain energy homeostasis, and promote cell survival during treatment [84].

The activation of protective autophagy is a principal mechanism in association with the success rate of chemotherapy as well as the development of chemoresistance [85]. In this context, the efficacy of 5-Fluorouracil (5-FU), which is a thymidylate synthetase-inhibiting chemo-drug to cure solid tumors, is limited as a consequence of protective autophagy stimulation [86]. Among multiple mechanisms described to explain the interplay between protective autophagy and 5-FU chemoresistance, Beclin 1-mediated conversion of LC3-I to LC3-II, JNK-facilitated phosphorylation of Bcl-2, and over-activation of the autophagy machinery are reported to be more responsible [65]. Temozolomide (TMZ) is another chemotherapeutic agent that acts by alkylating DNA to combat gliomas [87], and the induction of protective autophagy unfortunately attenuates its efficacy, as well [88]. Mechanistically, the up-modulation of the AMPK-ULK1 signaling, the extracellular signal-regulated kinase (ERK) cascade, mitochondrial and endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) generation are the major mechanisms leading to autophagy activation following the TMZ therapy [65,88]. The response to other chemotherapeutics such as cisplatin, paclitaxel, etc., an also be regulated by the induction of protective autophagy through a vast array of molecular mechanisms and signaling pathways related to autophagy [65].

In the case of radiation therapy, autophagy has been found to be inversely correlated with radioresistance. In other words, autophagy suppression can positively regulate the radiosensitivity in cancer cells, proposing the clinical application of autophagy inhibitors in cancer therapy [89]. In a group of solid tumors, such as osteosarcoma, the activated autophagy reduces post-irradiation ROS production, resulting in radioresistance [90]. Additionally, in glioblastoma (GBM), as well as head and neck carcinoma, the dual inhibitor of PI3K/mTOR, i.e. NVP-BEZ235, triggers radiosensitivity [91]. Cancer stem cells (CSCs) typically represent high degrees of radioresistance and autophagy blockade might help these cells become vulnerable to irradiation [[92], [93], [94]]. In line with this fact, radioresistant GBM stem-like cells (SLGCs) have been reported to have increased basal level autophagy in comparison to sensitive SLGCs [95,96]; thus, silencing the autophagy with an ATG5 small interfering RNA (siRNA) and a PI3K inhibitor such as 3-methyladenine (3-MA) enhances the radiosensitivity in GBM cells, particularly after the inhibition of signal transducer and activator of transcription 3 (STAT3) [97,98]. 3-MA-mediated inhibition of autophagy was also found to be beneficial in increasing the efficacy of radiotherapy in cell culture model of esophageal squamous carcinoma principally by potentiating the apoptotic flux [99].

As the other method of cancer therapy, targeted therapy, which focuses on specific targeting of tumor cells with the lowest degrees of adverse effects on non-cancerous tissues, is also in correlation with protective autophagy [16,100,101]. From this perspective, protective autophagy has been realized to be induced by bevacizumab, an angiogenic-inhibiting monoclonal antibody, to control ROS production, and thereby supporting cell survival in hepatocellular carcinoma (HCC) [102]. Autophagy-dependent resistance to HER2 inhibitors is another example, which provokes cell death evasion in breast cancer [103]. Given the other types of targeted therapeutics, namely small molecule inhibitors (SMIs), autophagy induction may restrict their efficacy; epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are a well-studied group of SMIs that are mechanistically affected by the stimulated autophagy, developing therapeutic resistance [104,105]. TKIs prescribed to combat chronic myeloid leukemia (CML) by interfering with the BCR/Abl oncogene have also been found to trigger protective autophagy in an intracellular calcium-dependent manner [16]. Moreover, sensitivity to the multi-TKI sorafenib can be restored through directing the protective autophagy to death-inducing autophagy in Akt-inhibited sorafenib-resistant HCC cells [106]. In the instance of the interplay between autophagy and hormonal therapy, the therapeutic effectiveness highly depends on the induction of protective autophagy, as well; a hypothesis that was evidenced by the LAMP3-mediated induction of autophagy in tamoxifen-resistant breast cancer [107]. Hence, the up-modulation of protective autophagy is significantly responsible for the expansion of resistance against targeted therapy in a wide variety of cancer models.

Considering the preceding paragraphs, it can be summarized that the efficacy of different cancer therapies is negatively affected by the induction of undesirable protective autophagy, and thus could be overcome by targeting the multiple levels of the autophagy flux, especially in combination with other effective therapeutics, such as immunotherapeutic approaches. Among different types of immunotherapies, using ICIs have clarified promising horizons in cancer eradication. Like all cancer therapeutic methods, ICI therapies encounter various limitations that can be removed or at least attenuated by parallel using of other effective procedures, a.k.a. combination therapies. Targeting autophagy is a potential proceeding in this framework that is specifically highlighted in the following sections.

3 Autophagy and immune checkpoint inhibitors

3.1 Immune checkpoint inhibitors, game-changers in cancer therapy

Under physiological circumstances, a set of immune checkpoints that are known as inhibitory and stimulatory mechanisms affecting the activity of immune cells, have been introduced to maintain the existing balance between pro- and anti-inflammatory signaling cascades as well as conserving the self-tolerance to principally avoid the onset and progression of autoimmune defects [[108], [109], [110]]. Nevertheless, these checkpoints can be employed by tumor cells to evade immune-related eradication [[111], [112], [113], [114], [115]]. Literally, malignant cells suppress tumor antigen expression, trigger T cell tolerance, and release immune suppressive cytokines to turn on inhibitory immune checkpoints [116]. By targeting these checkpoints, ICIs block their inhibitory signals to help the immune system identify and attack tumor cells; in other words, ICI drugs make the immune responses stronger to combat cancer and cancer cells [[117], [118], [119], [120]]. The discovery and approval of ipilimumab was a milestone in ICI therapy and introduced ICIs as new powerful therapeutic weapons to fight a variety of cancers. Unlike the conventional cytotoxic therapeutics, ICIs have improved the efficacy of the host immunity against malignancies [23].

Programmed cell death receptor-1 (PD-1), programmed cell death receptor-1 ligand (PD-L1), and cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) are the best known immune checkpoints to date [121]. PD-1, which can be up-modulated on activated T cells, attaches to PD-L1 as its ligand, and then restricts the activation of T cells by conducting an inhibitory signal [122]. CTLA-4, as another overexpressed molecule on activated T cells, also blocks the over-stimulation of T cells through T cell receptors (TCRs); in depth, in a competition with the TCR co-stimulatory receptor, CD28, CTLA-4 struggles to link to B7-1/2 ligands for further prevention of CD28-dependent T cell activation [122,123]. Since the oncogenic trait of the tumor microenvironment (TME) depends on the up-regulation of the above-stated molecules, their inhibition could result in the expansion of immune-related anti-tumor responses [124]. For a better understanding, ipilimumab (an anti-CTLA-4 monoclonal antibody) can be exemplified; as the first FDA-approved ICI, ipilimumab was being administered for those with advanced melanoma [125]. Later, anti-PD-1 and anti-PD-L1 drugs, including nivolumab, pembrolizumab, atezolizumab, avelumab, etc., were approved for a wide spectrum of solid and hematologic neoplasms [122,126,127]. Although these ICIs have promoted therapeutic responses, their effectiveness is limited and sometimes they encounter some degrees of resistance [128,129].

According to previous observational studies and clinical trials, there are three different patient populations in response to ICI therapies: responders, which primarily respond and continue to respond; patients with innate resistance that do not respond at all; and those with acquired resistance that respond at first but then develop cancer progression [[130], [131], [132], [133], [134]]. Due to the partial comprehension of the full aspects of clinical, molecular, and immunologic parameters related to clinical response to ICI therapy, the underlying mechanisms by which innate and acquired resistance are developed are not fully elucidated [130]. The central dogma of innate and acquired resistance will be more clarified by reviewing the horizons of the model of response-to-ICI, including the substantial steps that can be suppressed, bypassed, or even blocked in a tumor-dependent manner, or co-selected by stromal and immune ingredients of the TME.

Unsuccessful ICI therapy is principally caused by incomplete production of anti-tumor T cells, dysfunction or inadequate function of tumor-specific T cells, and/or defective expansion of T cell memory [130,133,134] (Fig. 3). In summary, incomplete formation of anti-tumor T cells is developed due to the absence of appropriate neoantigens, disrupted neoantigen processing, or weakened presentation of the antigens [133]. On the other front, various tumor-intrinsic and -extrinsic immune suppressive constituents of the TME are the processes explaining T cell dysfunction [131]. Intending to boost the response to ICI therapy, combination strategies, such as co-administration of anti-CTLA-4 drugs and anti-PD-1/PD-L1 agents, have been employed as one of the promising approaches. Despite the effectiveness of these strategies, the extent of toxicities is challenging [124]. In this regard, over-stimulation of the immune system causes side effects with an autoimmune pattern that may negatively impact diverse organs, leading to hospitalization and cessation of using drugs [135,136]. Furthermore, the next-generation of ICIs that have been designed and developed to target lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin-3 (TIM-3), B7-H3 and B7-H4 molecules, A2aR and CD73, natural killer group protein 2A (NKG2A), and poliovirus receptor-related immunoglobulin domain containing (PVRIG)/poliovirus receptor-related 2 (PVRL2) are being evaluated to enhance the efficacy of current ICI therapies [23,137,138]. Still, some limitations are predicted to disrupt the process of ICI therapy even with the next-generation inhibitors [138]. Thus, more effective and less toxic strategies should be applied to conquer the existing challenges attributed to ICI therapy.Fig. 3 Underlying mechanisms by which ICI-related therapeutic response and/or resistance can be developed. Innate or acquired resistance against ICIs is developed due to incomplete formation of anti-tumor T cells, defective expansion of memory T cells, and/or dysfunction of tumor-specific T cells. The absence of appropriate neo-antigens, disordered presentation of tumor antigens, and disrupted immune infiltration inside the tumor are considered the major contributors to incomplete T cell generation (Left). In the case of defective development of memory T cells, T cell epigenetic alterations and T cell exhaustion have been realized to be responsible (Middle). Ultimately, defects in IFN signaling, the presence of immune suppressive cells, and alternate immune checkpoints can result in tumor-specific T cell dysfunction (Right). It should be noted that this figure has illustrated the mechanisms related to ICI therapeutic response.

Fig. 3

The role of autophagy has been investigated in cancer, and a large number of studies have proposed that autophagy suppression may sensitize tumors to ICIs by releasing T cell-attracting chemokines along with other immunoregulatory mechanisms [[139], [140], [141]]. Thereby, targeting autophagy in conjugation with ICI therapies might improve the efficacy of conventional therapeutics to overcome therapy resistance.

3.2 Impact of autophagy on immune cell function, immune evasion and response

In tumor immunity, tumor cells serve as alloantigens, especially when they are planning to provide antigenic signals to T cells. The recognition of these malignant cells by TCRs on cytotoxic T lymphocytes (CTLs) is facilitated by major histocompatibility complex I (MHC-I) molecules expressed on the surface of the corresponding cells; the molecules that contain tumor-related antigenic peptides. Unfortunately, genetic mutations along with epigenetic alterations can disrupt MHC-I-antigen molecules, leading to cancer cell escape from the immune recognition. Antigen presentation in tumor cells or dendritic cells (DCs) is also affected by autophagy [142,143]. In this regard, T cell immunoglobulin- and mucin domain-containing molecule-4 (TIM-4) link to AMP-activated protein kinase α1 (AMPKα1) as well as activated autophagy-mediated removal of cancer cells, decreasing antigen presentation, impairing CTL responses, and enhancing immune tolerance [144]. Also, malignant cells might serve as antigen presenting cells (APCs), complicating the contribution of autophagy to endogenous antigen processing. Secretory autophagy, in which autophagosomes fuse with plasma membrane instead of lysosomes, can also transmit tumor-specific antigen signals, modulating the immune cells function. Dribbles (defective ribosomal products in blebs) are autophagosomes originated from tumor cells with a content of diverse molecules from DNA to proteins that can be considered hazardous signals [145]. When peripheral blood mononuclear cells (PBMCs) are experimentally loaded with Dribbles come from CMV-pp65 antigen-expressing tumor cells, virus-specific human memory T cells can efficiently be activated [145]. In addition, DRibbles isolated from APCs activate inflammasomes by supplying signals needed for the production of interleukin-1β (IL-1β). B lymphocytes loaded with DRibbles were found to present anti-tumor effects by triggering specific naive CD8+ T cell response [146,147]. Autophagosomes can also act as antigen carriers, which can be utilized in therapeutic cancer vaccination [148]. Considering the impact of autophagosomes derived from cancer cells on immune cell function, the secreted autophagosomes are proposed to affect stromal cells or adjacent tumor cells; a hypothesis that may uncover the immunological role of these autophagosomes to elucidate how secretory autophagy can participate in tumor immunity.

Beyond the effects of autophagy on immune cell function, it can substantially involve in the shaping process of both innate and adaptive immune systems. In this context, the under-expression of MHC-I was recently found to be regulated by an autophagy-dependent mechanism in pancreatic ductal adenocarcinoma [[149], [150], [151]]. Neighbor of BRCA1 gene 1 (NBR1) autophagy receptor conducts the MHC-I to be targeted to the lysosome, and thus total MHC-I levels were restored following the suppression of autophagy, NBR1, or the lysosome in in vitro and in vivo models of PDA [151]. The inhibition of progranulin, as a highly conserved regulator of lysosomal function, was also recognized to be responsible for the restoration of MHC-I expression in PDA cells principally through the suppression of autophagy [152]. Thereby, immune recognition and cancer cell eradication are strongly mediated by the autophagy-lysosome network (Fig. 4). Autophagy-mediated modulation of MHC-I is a specific process, arising from the recognition of aberrant posttranslational modifications (PTM) and is not translatable to MHC-II as well as the other cell surface markers [152,153]. Notwithstanding, further analyses such as global cell surface proteomics are needed to determine the full set of cell surface proteins affected by autophagy. Once autophagy is pharmacologically or even genetically inhibited across multiple cancer cell species, it sensitizes them to immune-mediated eradication [154]. Inflammatory cytokines, such as CCL5, CXCL5, and CCL10 have been found to mediate anti-tumor immune responses in autophagy deficient cancers [155,156]; an interesting finding that supports the hypothesis entitled autophagy inhibition may increase the apparentness of tumors by immune cells. More interestingly, the role of autophagy inhibition in triggering the tumor necrosis factor α (TNFα)-regulated T cell-mediated elimination of tumor cells has also been uncovered by a vast array of genome-wide CRISPR investigations [[157], [158], [159]]. Thoroughly, all these findings focused on the obscure involvement of autophagy in cessation of immune-mediated tumor eradication.Fig. 4 A schematic view of how autophagy correlates with immune evasion of tumor cell.

Fig. 4

In the case of connection between autophagy and immune response, the autophagy flux can either negatively or positively modulate immune reactions in response to cancer cells. Autophagy triggers T cell survival, and thus maintains ER homeostasis by controlling the content of calcium ions inside the T cells, while autophagy blockade promotes T cell death. Once autophagy is activated, the antigen presentation of DCs and T cell priming is enhanced, resulting in tumor growth deceleration [90]. In response to radiation therapy, as a conventional therapeutic approach to fight cancer cells, autophagy begins to deplete natural ligands of mannose-6-phosphate receptor (MRP), leading to its translocation to the cell surface and subsequent triggering of T cell-mediated eradication together with CTLA-4 immunotherapy in B16F10-bearing tumor model [160]. In response to temozolomide (TMZ) chemo-drug in GL261 glioma cells, autophagy activation can enhance T cell activity. Besides the autophagy-mediated T cell activation, autophagy stimulation also gives rise to NK cell-dependent elimination through homeobox containing 1 (HMBOX1) modulation in HepG2 cells or p53 activation in breast cancer cells [160,161]. In detail, CP31398-mediated reactivation of mutant p53 induces autophagy in breast cancer cells. CP31398 actually prevents lysosomes and autophagosomes to be fused. It also blocks the degradation of granzyme B, as a substantial determinant of NK cell killing [161].

Unlike the aforementioned findings, a group of studies believe that autophagy induction blocks T cell activation in response to chemotherapy [162], as well as epithelial-to-mesenchymal transition (EMT), which results in tumor growth and progression due to disordered T cell-mediated eradication [144,163]. In the absence of APC-associated antigen presentation, T cells priming is disrupted, and further induction of autophagy in macrophages or DCs triggers lysosomal antigen degradation, diminishing T cell killing that promotes tumor growth [144,163]. Chemo-treated cancer cells release danger-associated molecular patterns (DAMPs) to up-regulate TIM-4 on the surface of macrophages and DCs, and TIM-4 itself interacts with AMPKα1 following the autophagy activation. Using chloroquine, as a well-known autophagy inhibitor, causes an increase in CD8+ T cell-mediated killing of colon cancer cells as well as CD4+ T cell-mediated elimination of lung cancer cells. SKI-like proto-oncogene (SKIL)/tafazzin (TAZ)-induced autophagy can block the stimulator of interferon genes (STING) pathway-related immune responses against tumor cells. In parenthesis, SKIL enhances the stability of TAZ protein through down-modulation of LATS2 to induce autophagy in lung cancer. Furthermore, SKIL/TAZ/autophagy cascade suppresses the release of CXCL10, CCL5, and IFN-β, as pro-inflammatory cytokines to activate the STING pathway-triggered immune response against tumor [93,164]. Concurrent with autophagy activation, IL-1β release is decreased, directing the IL-1/Toll-like receptor/nuclear factor κB (IL-1/TLR/NF-κB)-mediated secretion of pro-inflammatory cytokine to be blocked in macrophages and DCs, which in turn causes an impaired γδ T cell activation [[165], [166], [167]]. Chloroquine can also be used in combination with IL-2 to boost IL-1 immunotherapy in metastatic model of liver cancer [168]. In consequence, autophagy has the ability of repressing pro-inflammatory response-mediated immunotherapy against tumors. Above the autophagy-related down-modulation of T cells, CLL5 is over-stimulated in the absence of autophagy activation, leading to NK cell infiltration followed by tumor growth deceleration in melanomas [169]. Under the hypoxic conditions caused by breast cancer, in vitro activated autophagy initiates the degradation of granzyme B to cause an undesirable resistance against NK cell-mediated killing. Together, once autophagy is triggered in APCs or tumor cells, it impedes the activity of immune cells, whose their functions conduct processes such as antigen presentation or granzyme B degradation. Hence, it can be concluded that autophagy induction not only regulates immune responses in a positive manner but also may negatively modulate anti-tumor immune responses.

Surprisingly, autophagy has been found to synergize with dual ICIs therapy (i.e. anti-PD1 and anti-CTLA4 antibodies) to improve the immune responses against cancer cells by up-regulating the MHC-I molecules [162,170]. In the following section, the ambiguous aspects of the existing crosstalk between autophagy and immune checkpoint molecules/mechanisms will be uncovered to highlight the possible effectiveness of autophagy-ICIs combination therapies.

3.3 Interplay between autophagy and immune checkpoint pathways

Regarding the rationale of combination autophagy inhibitors with ICIs, it should be noted that cancer cells are not solitary units; they are in constant interaction with the intricate network of cells and substances that make up their immediate environment [171]. The TME is pivotal at various cancer stages, including its onset, spread, resistance to therapy, and interaction with the immune system [172]. It plays a significant role in both the immune system's monitoring of the tumor and the tumor's evasion of immune detection [[173], [174], [175], [176]]. The TME hosts a variety of immune cells, such as CD8+ and CD4+ T cells, Tregs, B cells, neutrophils, TAMs, NK cells, and DCs. These cells are essential in the dynamic between the tumor and the immune system. Cancer cells present various markers on their surface, including immune checkpoint molecules, which are crucial for self-tolerance and immune regulation, thus enabling the immune system to combat tumors. Nevertheless, cancer cells may utilize these molecules to escape immune detection [177,178]. Two primary mechanisms facilitate immune evasion by cancer cells: One, the disruption of the bond between the MHC molecules on APCs and the TCR impedes antigen presentation and T cell activation [179], and two, the interruption of pathways controlled by co-stimulatory and co-inhibitory molecules, known collectively as immune checkpoints, can also result in immune evasion. Many cancers exhibit a reduction in MHC-I presentation, a vital element for effective antigen presentation, correlating with a negative prognosis [180]. Additionally, the interaction of specific co-inhibitory receptors on T cells, such as CTLA-4 and PD-1, with their respective ligands (B7-1/B7-2 for CTLA-4 and PD-L1 for PD-1) on cancer cells, can inhibit T cell activation and restrict their ability to target tumor cells [[181], [182], [183]].

In the past few decades, ICIs have become a notable strategy in cancer treatment by blocking the inhibitory signals from cancer cells to T cells, thus revitalizing the immune system's attack on tumors [[184], [185], [186]]. Various ICIs targeting CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, and cemiplimab), and PD-L1 (atezolizumab, avelumab, durvalumab) have been approved for treating more than 50 cancer types [128]. These ICIs can be used alone or in conjunction with chemotherapy, as either primary or secondary treatment options.

Emerging research indicates that autophagy significantly influences the immune response [[187], [188], [189], [190]]. Autophagy can aid immune evasion by targeting MHC-I molecules for degradation [141], a process facilitated by the autophagy cargo receptor NBR1, resulting in reduced MHC-I presentation on cancer cells, thus obstructing antigen presentation and T cell cytotoxicity. Moreover, autophagy can affect the functionality of different immune cells within the TME. For instance, a lack of autophagy in tumor cells can increase PD-L1 expression and dampen T cell-mediated cytotoxicity [191]. On the other hand, inhibiting PPT1, an enzyme involved in autophagic degradation, can boost T cell priming by encouraging IFN-β release from macrophages and the transition from M2 to M1 phenotype [192]. Inhibiting autophagy also seems to improve the performance of NK cells and DCs in the TME, leading to greater infiltration and cytotoxicity against cancer cells [169,193]. Moreover, blocking autophagy may reprogram TAMs from an immunosuppressive M2 phenotype to a pro-inflammatory M1 phenotype, thereby strengthening the overall anti-tumor immune response [194].

The swift sanctioning of ICIs for oncological applications, favored for their superior risk-to-benefit ratio over conventional treatments, does not guarantee universal effectiveness [180]. Solo ICI treatments have yielded limited success, with response rates seldom surpassing 40 % in specific malignancies. Moreover, ICI-based combination therapies have been linked to an increase in immune-related complications [131]. Such constraints have catalyzed investigations into synergistic approaches, particularly incorporating autophagy blockers to amplify ICI efficacy.

PD-L1, as the PD-1 ligand, is a molecule with immunosuppressive capacities that is expressed on the surface of cancer cells as well as the membrane of immune cells. Immunosuppressive effects of PD-L1 are unveiled when the molecules are bound to their receptor, PD-1, on the surface of T cells, which in turn block the proliferation of these immune cells [195]. Both in vitro and in vivo assessments have confirmed that autophagy can down-regulate the PD-L1. By degrading immune checkpoints as well as controlling the cytokine release, autophagy can modulate immunotherapy (Table 1). As one of the accepted mechanisms, autophagy decides to degrade damaged DNA, disordered proteins, and expired organelles to sustain standard cell conditions for triggering anti-tumor immunity. Negatively, autophagy also has negative roles in the induction of tumor cell monitoring [196,197], as it provokes immune evasion of cancer cells due to the blockade of mTOR signaling, which leads to autophagy activation.Table 1 The crosstalk between autophagy and immune checkpoint mechanisms based on in vitro evaluations.

Table 1Immune checkpoint molecule/mechanism	Target gene/protein/signaling pathway	Autophagy status	Type of cancer	Cancer-related outcome	Reference	
PD-L1 ↓	p62/SQSTM1/NF-κB	Inhibited	Gastric cancer	Tumor progression	[202,203]	
PD-L1 ↓	p62	Inhibited	Ovarian epithelial cancer	Platinum chemo-resistance	[225]	
PD-L1 ↓	STAT3	Activated	NSCLC	–	[206]	
PD-L1 ↓	HIP1R	Activated	NS	Immune-mediated eradication of tumor cells	[208,209]	
PD-L1 ↑	SIGMA I	Inhibited	TNBC
Prostate cancer	Cancer progression	[[210], [211], [212]]	
PD-1/PD-L1	Vps34	Activated	NS	Tumor immune evasion	[140,213]	
PD-L1 ↑	ATG7	Activated (degrades FOXO3)	Bladder cancer	Tumor invasion	[214]	
CTLA-4 ↑	PI3K/Akt/mTOR	Inhibited	Melanoma	Therapeutic resistance against anti-CTLA-4 Ab	[226]	
CTLA-4 ↑	PI3K/Akt/mTOR	Inhibited in DCs	NS	Disruption of antigen presentation and T cell activation	[227]	
NS: Not specified.

The autophagy-mediated regulation of PD-L1 expression is orchestrated through multiple mechanisms with the participation of diverse genes and proteins. P62/SQSTM1 is one of those proteins with multifaceted activities that modulates cell vital processes such as signal transduction, survival, and apoptosis [198,199]. P62 that is intrinsically known as a ubiquitin-binding protein, has been observed to be responsible for the regulation of several signaling pathways, as well as the autophagy flux. Through the autophagy, p62 is degraded inside the cytoplasm and is accumulated concurrent with autophagy dysfunction. Indeed, p62 is a reflector of autophagy activity and is inversely correlated with degradative capacity of autophagy [200,201]. Following the p62-induced autophagy, a variety of tumor-provoking pathways such as NF-κB signaling are activated; in gastric cancer, it has been demonstrated that PD-L1 expression is modulated through the p62/SQSTM1-/NF-κB signaling. Using autophagy inhibitors and small interfering RNA (siRNA), PD-L1 can be overexpressed, leading to p62 accumulation and NF-κB over-activation. The accumulated p62 still trigger tumor progression by subsequent activation of NF-κB and other downstream mechanisms. As a consequence, autophagy and p62 can form a cooperative network to support tumor growth and development. The corresponding network can also orchestrate the chemotherapeutic response; for instance, platinum-resistant ovarian epithelial cancer cells have been reported with high expression levels of p62, which is under-expressed when an autophagy stimulator is applied, sensitizing the tumor cells to platinum [202,203]. Therefore, targeting autophagy with subsequent modulation of p62 can be considered an approach to autophagy-ICI combination therapy [204].

In line with the findings reviewed about p62, STAT3 is also of great significance in modulating the nexus between autophagy and PD-1/PD-L1 immune checkpoint pathway. In response to tumor-stimulating signals, STAT3 is up-regulated to switch on target genes for subsequent induction of tumor growth [205]. The mentioned up-modulation of STAT3 has been shown to increase PD-L1 expression, to help cancer cells escape from the immune killing. STAT3 is inversely correlated with tumor autophagy, as its over-stimulation blocks the autophagy flux, and vice versa; whilst it can activate autophagy if becomes dephosphorylated [201]. According to the study conducted by Tang et al., miRNA-3127-5p-mediated phosphorylation of STAT3 that results in autophagy inhibition, specifically through blocking the autophagosome generation, over-activate PD-L1 in cell culture model of non-small cell lung carcinoma (NSCLC) [206], suggesting the pivotal role of this miRNA in lung cancer chemotherapeutic resistance with the contribution of STAT3-autophagy-PD-L1 nexus. Accumulating evidence suggests that PD-L1 is also expressed on the Golgi apparatus (GA) and related vesicles other than the cancer cell surface [207]. PD-L1 molecules that are located on the surface of tumor cells are responsible for the repression of immune escape and stimulation of the oncogenic processes. Huntingtin-interacting protein 1-related protein (HIP1R), which is a PD-L1-binding autophagy receptor, targets the PD-L1 to be degraded by the autophagy-lysosome pathway, which in turn potentiates the immune killing effects of immune cells. In the absence of HIP1R, autophagy is down-modulated, while PD-L1 is overexpressed [208,209]. There are a group of proteins that can stabilize PD-L1 by blocking its autophagic lysosomal degradation. SIGMA I (integrated membrane scaffold protein) is one of those proteins that interacts with glycosylated PD-L1 to increase PD-L1 content in in vitro models of triple-negative breast cancer (TNBC) and prostate cancer [210,211]. RNAi-mediated silencing of SIGMA I results in PD-L1 under-expression. This event is also caused by using the SIGMA inhibitor, IPAG [1-(4-chlorophenyl)-3-(2-adamantyl) guanidine]. In detail, IPAG stimulates autophagy, up-regulates LC3B, suppresses the PD-L1 expression, and over-activates T-cells, suggesting the autophagy-mediated degradation of PD-L1 [212].

The process of autophagosome formation, which is central to the whole autophagy, is controlled by a type III PI3K (PIK3C3), Vps34, in a complex network with Vps15/Atg14/UVRAG/Beclin1 (Fig. 1); thus, the initiation step of autophagy substantially depends on the presence of Vps34 [140]. Regarding the considerable role of Vps34 in autophagy progression, it can be targeted for autophagy blockade to cease the process of tumor immune efficacy of PD-1/PD-L1 immune checkpoint disruption [213]. Since immune cell dysfunction in the TME triggers the immune evasion of cancer cells, Vps34 inhibition could recruit immune cells by promoting the expression and release of particular chemokines (i.e. CCL5 and CXCL10) from tumor cells and tissues [140]. In this context, combining antibodies to PD-1 and PD-L1 with Vps34 inhibitors represented more efficient therapeutic effects in a mouse model of tumorigenesis.

In bladder cancer, ATG7 overexpression can result in autophagy-mediated removal of forkhead box transcription factor O3 (FOXO3) and the subsequent inhibition of miR-145, which in turn up-regulates the PD-L1 [214]. Literally, once miR-145 is under-expressed, it is no longer linked to the 3′-UTR of PD-L1 mRNA, which leads to stabilization of the corresponding mRNA. The stabilized and over-expressed PD-L1 protein then increases the invasiveness of bladder cancer cells [214].

Research indicates that NSCLC patients with liver kinase B1 (LKB1) mutations respond inadequately to anti-PD-1 therapy. This lack of response may stem from heightened autophagic activity in LKB1-deficient tumors, which leads to the breakdown of antigen-processing systems and diminished MHC presentation. Deng and colleagues found that obstructing ULK1 (via MRT68921) or lysosomal operations hinders the autophagic destruction of immunoproteasome elements, thereby reinstating antigen presentation and bolstering T cell presence in LKB1-mutant NSCLC mouse models, culminating in a bettered reaction to anti-PD-1 therapy [215].

Amaravadi et al. observed that merging hydroxychloroquine (HCQ) with anti-PD-1 therapy curtails tumor expansion and prolongs survival in melanoma rodent models [192]. Chemically impeding PPT1, a controller of autophagy, shifts macrophages from an immunosuppressive M2 type to a cancer-destroying M1 form, enhancing T-cell-driven toxicity. Moreover, PPT1 blockade considerably lessens the infiltration of myeloid-derived suppressor cells within the TME. Additionally, PPT1-lacking DCs seem to better prime naive CD8+ T cells during viral immune reactions, hinting at improved DC functionality post-autophagy inhibition [193].

Recent findings also underscore the promise of merging the PPT1 blocker GNS561 with anti-PD-1 therapy to rejuvenate the immune response in a genetically modified, immunocompetent HCC mouse model [216]. This duo elevates MHC-I expression on cancerous cells, prompting the reoccupation of the tumor locale by cytotoxic T cells. Presently, a phase 2 clinical trial (NCT05448677) is underway to gauge the safety and effectiveness of GNS561 in conjunction with atezolizumab and bevacizumab for the initial management of inoperable HCC, marking the inaugural clinical evaluation of an autophagy inhibitor (PPT1 blocker) in synergy with immunotherapy.

The other immune checkpoint is CTLA-4, whose role in tumor immunity and autophagy has been confirmed in melanoma. Anti-CTLA-4 antibodies can potentiate anti-tumor immune responses. The PI3K/AKT/mTOR signaling pathway that accounts for autophagy inhibition, is undesirably activated in several cancers, and thereby provokes cancer progression [217,218]. CTLA-4 has the ability of triggering the aforementioned signaling to suppress the transcription of proteins required for autophagosome formation, thus blocking the autophagy, while increasing T cell survival. Accordingly, CTLA-4 inhibition by particular antibodies (i.e. anti-CTLA-4 ICIs) reverses the activation of PI3K/AKT/mTOR by down-regulating the ATGs. It has been proposed that autophagy is correlated with CTLA-4 receptor and ligand in an autophagy-PD-L1-like manner [218,219]. In CTLA-4 inhibitor-resistant but not PD-1 inhibitor-resistant melanoma, autophagy inhibition is strongly correlated with cancer-related germline antigens. As a consequence, autophagy inhibition principally contributes to therapeutic resistance against CTLA-4 ICIs. Thus, targeting autophagy in conjugation with CTLA-4 inhibition might provide more efficient therapies against diverse tumors [220]. Consistently, pharmacological inhibition of PI3Kβ has been found to boost the efficacy of anti-PD-1 as well as anti-CTLA-4 therapies, which indicates synergistic effects between ICIs and PI3K-AKT-mTOR signaling. On the other hand, PI3K/Akt/mTOR stimulation caused by CTLA-4 can suppress autophagy in DCs, disrupting the process of antigen presentation and T cell activation. Owing to this finding, a possible connection can be explained between FOXP3+ Tregs and DCs presenting antigens in a CTLA-4-dependent manner, which in turn modifies the autophagy flux. In clinical settings, autophagosome formation is blocked following the treatment of DCs with CTLA-4 antibodies, and thereby autophagy is attenuated [221]. Together, autophagy-CTLA-4 ICI combination therapy may provide more potent anti-tumor T cell immunity.

The Yamamoto group discovered that CQ administration bolsters MHC antigen display in PDAC models. This improvement leads to increased CD8+ T cell growth, activation, and malignant cell eradication. Although CQ alone did not markedly affect tumor size, its use in tandem with anti-PD-1 and anti-CTLA4 treatments resulted in a combined anti-cancer effect and intensified immune response against tumors in rodents [141].

Recently, different approaches are developed for further potentiation of autophagy to increase immunogenic cell death (ICD). Within this context, using low-dose chemotherapeutics in combination with rapamycin, as an autophagy stimulator, has been determined to induce T-cell immunity against tumors. Low-dose rapamycin therapy also enhances neoantigen-specific immune cell responses, accompanied by the modification of the TME [222]. ATG5 silencing declines the release of high mobility group box 1 protein (HMGB1), and the subsequent early inhibited autophagy decreases ICD, while late inhibition can increase ICD, depending on the response of secretory autophagy. Co-administration of ICD stimulator and autophagy inhibitor positively increases the ICD-dependent immunity against multiple malignancies, such as colon cancer [223,224]. This combining strategy has opened up new avenues to cancer immunotherapy. Advantages of ICI-autophagy inhibitor convergence include diminished exhaustion of cytotoxic T cells, transition of TAMs from M2 to M1 phenotype, refined antigen presentation, and strengthened immune response against tumors. Albeit preclinical trials signal potential in the ICI-autophagy inhibitor alliance, extensive clinical trials are essential to substantiate these preliminary outcomes [180].

4 Preclinical evidence: autophagy inhibitors in combination with ICIs

One of the most common circumstances leading to ICI resistance is cold TME that is characterized by the lack of T cells with tumor-infiltrating features as well as the engagement of immunosuppressive cells. As mentioned previously, targeting autophagy facilitates the remodeling of TME to regulate tumor-killing immune responses. It is a fact that supports the significance of combination therapies to increase ICIs efficacy.

Among a variety of in vitro and in vivo assessments to confirm the effectiveness of autophagy-ICI combination therapies, Sharma et al. revealed that chloroquine in conjugation with dual ICI therapy could significantly increase the potential of immune cells to eradicate tumors [224]. Furthermore, co-administration of SIRPα-Fc and chloroquine was found to disrupt the CD47/SIRPα axis to suppress the protective autophagy in tumor cells, then increased the phagocytosis of macrophages, and finally triggered CD8+ T cell-mediated immunity against cancer cells [228,229]. Above that, hydroxychloroquine and rapamycin co-treatment inhibits autophagy along with the under-expression of CD47 and SIRPα, to increase the phagocytosis of tumor-associated macrophages. Concurrent utilization of hydroxychloroquine and rapamycin also enhance the efficacy of anti-PD-1 therapy through converting the M2-like macrophages into M1-like cells [230]. In this framework, palmitoyl protein thioesterase 1 (PPT1) is a newly identified autophagy modulator that boosts cancer-eradicating immune responses through the aforementioned macrophage switching and enhancing T cell-mediated cytotoxicity [231].

By repressing the ATGs, including Beclin1 and Vps34, CCL5 and CXCL10 pro-inflammatory cytokines are released into the melanoma and colon cancer-related TME by modulating the STAT1/IRF7 signaling, which causes immune effector cells to be infiltrated. Using Vps34 inhibitors can sensitize in vitro models of melanoma and colon cancer to PD-1/PD-L1 ICI, and also produce active immune TMEs [232]. Researchers found a promising autophagy inhibitor, ESK981, which sensitizes prostate cancer cells to ICIs. It has been determined that ESK981 acts by releasing CXC10 to draw T cells [233].

In metastatic NSCLC, the conventional PEM/CDDP chemotherapy was not effective in combination with ICIs, while the combination with mitogen-activated protein kinase kinase inhibitor (MEKi) suppressed the autophagy flux and triggered the recruitment of CTLs for further eradication of tumor cells [234]. In tumor models with mutated LKB1, the production of immune peptides is inhibited; the suppression of Unc-51-like kinase 1 (ULK1), as an autophagy modulator, can reverse these conditions by enhancing the immunoproteasome expression [235]. Together, autophagy inhibitors make CTLs to be infiltrated into the TME, resulting in an improved ICI therapy.

Considering the novel approaches of combination therapies, a group of cancers have been recognized to benefit from CTL activation caused by ICI over-stimulation [236]. Learning to how manipulate immune checkpoint mechanisms has revolutionized the immunotherapy of solid tumors and the development of conventional ICIs was a milestone in this context.

Later, autophagy inhibitors, such as chloroquine, which had been confirmed as anti-tumor agents, were found to be more effective against tumors when used in combination with mono- or dual ICI therapy by inhibiting the autophagy-mediated elimination of MHC-I [237,238]. Although there are no clinical evaluations confirming the co-administration of autophagy modulators and ICIs, it has been suggested that targeting autophagy combined with chemo-immunotherapy, especially using MNPs as integrative multifunctional nanoparticles, provides high degrees of stability, biocompatibility, and encapsulation efficiency [239,240], to enhance the therapeutic efficacy and overcome the existing resistance against individual therapies.

5 Limitations and future directions

Inhibiting autophagy is increasingly recognized as a viable approach in oncology, especially when used in tandem with other therapeutic modalities. Early-stage research with various autophagy-blocking agents has yielded promising outcomes, demonstrating significant anti-tumor effects and low toxicity at reduced dosages. Nonetheless, the transition from preclinical success to clinical application has been challenging, with some trials showing adverse effects and limited effectiveness [180].

The primary obstacle has been the lack of specificity in previously tested autophagy blockers, as they were not originally developed for this purpose. However, recent advancements have introduced a new wave of autophagy inhibitors, specifically engineered for cancer therapy, which are currently undergoing clinical evaluation. These novel inhibitors show great potential, particularly when paired with ICIs, to reactivate cytotoxic T cells and modify the behavior of TAMs to combat cancer. Presently, GNS561 is the only autophagy inhibitor under phase 2 clinical investigation in conjunction with atezolizumab and bevacizumab [180].

The combination of autophagy inhibitors and immune checkpoint inhibitors in cancer therapy is a complex strategy that aims to enhance the effectiveness of treatment. However, there are several challenges and limitations associated with this approach, including the presence of few T cells (“immune-cold” tumors) and a high number of immunosuppressive cells in the TME can limit the effectiveness of combination therapy, primary and secondary resistance to single-agent immunotherapy often results in treatment failure, and only a minority of patients experience long-term benefits, novel strategies need to be investigated for subgroups of patients with low expression of PD-L1, as there is a lack of overall survival benefit of immune checkpoint inhibitor–based regimens in the first-line setting versus chemotherapy alone. The challenge and development of targeting cytoprotective autophagy as a cancer therapeutic approach in clinical application need further study. Furthermore, autophagy plays a role in therapeutic resistance, and the limitations of available autophagic inhibitors in cancer treatment need to be addressed [[241], [242], [243], [244]].

MEK inhibitors (MEKi), akin to ICIs, have demonstrated encouraging preclinical efficacy but have fallen short in clinical settings [245]. Intriguingly, inhibiting the KRAS-RAF-MEK-ERK signaling cascade has been found to induce autophagy, thereby shielding cancer cells from the adverse effects of KRAS pathway disruption [246]. DCC-3116, a molecule designed to counteract this autophagy upsurge, has shown potential in augmenting the anti-cancer effects of trametinib (a MEKi) in laboratory studies [247], underscoring the prospective synergy of autophagy blockers with MEKi in clinical research (NCT04892017).

Despite being in the nascent stages, the strategy of targeting autophagy in cancer therapy remains persuasive, more so when integrated with targeted treatments and MEKi. Emerging research avenues have also come to light. Recent breakthroughs in understanding autophagosome genesis have pinpointed TMEM41B deficiency as a factor in disrupted autophagy initiation and lipid utilization [248,249]. Moreover, ATG9A and ATG2A have been identified as key players in autophagosome construction during the elongation phase [250].

Recent findings emphasize the critical role of protein phosphorylation in autophagy regulation. The phosphorylation of VTI1B by PTPN9 [251]and syntaxin 17 by TBK1 [252] is vital for the growth of autophagic structures and the formation of the ULK1 complex, which governs autophagosome creation. Furthermore, Klionsky and colleagues have demonstrated that ATG14 not only activates the ULK1 complex but also oversees the fusion of autophagosomes with lysosomes, highlighting the intricate functions of autophagy-related protein variants and the therapeutic potential of targeting specific variants [180].

The advent of proteolysis-targeting chimeras (PROTACs) marks an innovative direction for crafting autophagy inhibitors [253]. This approach holds the promise of engaging previously intractable proteins, offering advantages such as reversibility, heightened specificity, and reduced dosage needs [254]. Despite ongoing developmental challenges, particularly their substantial molecular size, PROTACs present considerable potential for modulating autophagy and other pivotal pathways in cancer treatment and immune cell activation [180].

The pursuit of autophagy as a target in cancer therapy continues to be a dynamic field of study, with the advent of more precise autophagy inhibitors, combined regimens with ICIs and MEKi, and the exploration of innovative methods like PROTACs, paving the way for surmounting existing barriers and forging more efficacious cancer treatments.

6 Conclusions

Despite the effectivity of ICIs in immunotherapeutic cessation of cancers, they represent degrees of insufficiency as tumors may evade the immune system and do not respond to conventional therapies due to their intrinsic or acquired resistance. Many combination therapies have been proposed and evaluated by clinical trials to minimize or even eradicate tumor resistance against ICIs, however most of them were not so beneficial. In recent years, researchers noticed that targeting autophagy in combination with applying conventional ICIs, including anti-PD-1/PD-L1 and anti-CTLA-4 antibodies, can boost the potential and efficacy of theses immunotherapies in fighting different malignancies. Within the context, autophagy induction has been found to be a promising tool to improve tumor immunotherapy based on the autophagic elimination of PD-L1. Thus, the immune checkpoint PD-L1 is almost completely blocked and tumor cells have no longer access to those molecules. Furthermore, the stimulation of autophagy also accelerates the blockade of CTLA-4, as it undergoes recycling to the cell surface and is packaged for further lysosomal degradation. Autophagy activation affects the antigen production and T cell activation, as well. Notwithstanding, no approved autophagy-ICI combination therapy has been introduced to cure a particular cancer type, and also some investigations believe that autophagy can undesirably cause tumor immune evasion. Thus, further experimental studies as well as clinical trials are still needed to confirm possible benefits of using ICIs in combination with autophagy regulators in treating ICI-resistant tumors.

Funding

Not applicable.

Data availability

Not applicable.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

CRediT authorship contribution statement

Mehrdad Hashemi: Conceptualization. Elaheh Mohandesi Khosroshahi: Writing – original draft. Mahsa Tanha: Writing – original draft, Methodology. Saloomeh Khoushab: Data curation, Conceptualization. Anahita Bizhanpour: Resources, Investigation. Farnaz Azizi: Writing – original draft, Conceptualization. Mahsa Mohammadzadeh: Writing – original draft, Formal analysis. Arash Matinahmadi: Resources, Formal analysis. Zeinab Khazaei Koohpar: Visualization, Software. Saba Asadi: Visualization, Investigation. Hengameh Taheri: Software, Resources. Ramin Khorrami: Writing – review & editing. Marzieh Ramezani Farani: Validation. Mohsen Rashidi: Supervision. Mahdi Rezaei: Supervision. Eisa Fattah: Supervision. Afshin Taheriazam: Supervision. Maliheh Entezari: Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

AMPK AMP-activated protein kinase

APC Antigen presenting cell

ATG Autophagy-related protein

Atg Autophagy-related gene.

BAG3 Bcl2-associated athanogene 3

BIF Bax-interacting factor

CML Chronic myeloid leukemia

CRC Colorectal cancer

CSC Cancer stem cell

CTL Cytotoxic T lymphocyte

CTLA-4 Cytotoxic T lymphocyte-associated molecule 4

DAMP Danger-associated molecular pattern

DC Dendritic cell

Dribbles Defective ribosomal products in blebs

EGFR-TKIs Epidermal growth factor receptor – tyrosine kinase inhibitor

EMT Epithelial-to-mesenchymal transition

ER Endoplasmic reticulum

ERK Extracellular signal-regulated kinase

FOXO3 Forkhead box O3

GA Golgi apparatus

GBM Glioblastoma

HCC Hepatocellular carcinoma

HIP1R Huntingtin-interacting protein 1-related protein

HMBOX1 Homeobox containing protein 1

HMGB1 High mobility group box 1 protein

ICD Immunogenic cell death

ICI Immune checkpoint inhibitor

IFN-β Interferon β

IL-1β Interleukin 1β

LAG-3 Lymphocyte activation gene 3

LAMP Lysosomal-associated membrane protein

LATS2 Large tumor suppressor kinase 2

LC3 Light chain protein 3

LKB1 Liver kinase B1

MEKi Mitogen-activated protein kinase kinase inhibitor

MHC Major Histocompatibility complex

MNP Magnetic nanoparticle

MRP Mannose-6-phosphate receptor

mTOR Mammalian target of rapamycin

NBR1 Neighbor of BRCA1 gene 1

NF-κB Nuclear factor κB

NKG2A Natural killer group protein 2A

NSCLC Non-small cell lung cancer

OS Oxidative stress

PBMC Peripheral blood mononuclear cell

PD-1 Programmed cell death receptor-1

PDA Pancreatic ductal adenocarcinoma

PD-L1 Programmed cell death ligand-1

PE Phosphatidylethanolamine

PI3K Phosphoinositide 3-kinase

PPT1 Palmitoyl protein thioesterase 1

PTM Post-translational modifications

PVRIG Poliovirus receptor-related immunoglobulin domain containing

PVRL2 Poliovirus receptor-related 2

SIRPα Signal-regulatory protein α

SKIL SKI-like proto-oncogene

SLGC Stem-like glioma cells

SMI Small molecule inhibitor

SQSTM1 Sequestosome-1

STAT Signal transducer and activator of transcription

STING Stimulator of interferon genes

TAM Tumor-associated macrophage

TAZ Tafazzin

TCR T cell receptor

TIM T cell immunoglobulin

TLR Toll-like receptor

TME Tumor microenvironment

TMZ Temozolomide

TNBC Triple negative breast cancer

TNFα Tumor necrosis factor-α

TSA Tumor-specific antigen

ULK1 Unc-51-like kinase 1

UTR Untranslated region

UVRAG UV radiation resistance-associated protein

Vps34 Vacuolar protein sorting 34
==== Refs
References

1 Ward R.A. Fawell S. Floc’h N. Flemington V. McKerrecher D. Smith P.D. Challenges and opportunities in cancer drug resistance Chem. Rev. 121 6 2020 3297 3351 32692162
2 Labrie M. Brugge J.S. Mills G.B. Zervantonakis I.K. Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer Nat. Rev. Cancer 22 6 2022 323 339 35264777
3 Wang X. Zhang H. Chen X. Drug resistance and combating drug resistance in cancer Cancer Drug Resistance 2 2 2019 141 34322663
4 Marine J.-C. Dawson S.-J. Dawson M.A. Non-genetic mechanisms of therapeutic resistance in cancer Nat. Rev. Cancer 20 12 2020 743 756 33033407
5 Sharma M. Bakshi A.K. Mittapelly N. Gautam S. Marwaha D. Rai N. Recent updates on innovative approaches to overcome drug resistance for better outcomes in cancer J. Contr. Release 346 2022 43 70
6 Pucci C. Martinelli C. Ciofani G. Innovative approaches for cancer treatment: current perspectives and new challenges Ecancermedicalscience 13 2019
7 Taghvimi S. Vakili O. Soltani Fard E. Khatami S.H. Karami N. Taheri‐Anganeh M. Exosomal microRNAs and long noncoding RNAs: novel mediators of drug resistance in lung cancer J. Cell. Physiol. 237 4 2022 2095 2106 35128660
8 Movahedpour A. Khatami S.H. Khorsand M. Salehi M. Savardashtaki A. Mirmajidi S.H. Exosomal noncoding RNAs: key players in glioblastoma drug resistance Mol. Cell. Biochem. 476 2021 4081 4092 34273059
9 Salehi M, Vafadar A, Khatami SH, Taheri-Anganeh M, Vakili O, Savardashtaki A, et al. Gastrointestinal cancer drug resistance: the role of exosomal miRNAs. Mol. Biol. Rep‥1-12.
10 Aman Y. Schmauck-Medina T. Hansen M. Morimoto R.I. Simon A.K. Bjedov I. Autophagy in healthy aging and disease Nature Aging 1 8 2021 634 650 34901876
11 Eskelinen E.-L. Autophagy: supporting cellular and organismal homeostasis by self-eating Int. J. Biochem. Cell Biol. 111 2019 1 10 30940605
12 Ghavami S. Zamani M. Ahmadi M. Erfani M. Dastghaib S. Darbandi M. Epigenetic regulation of autophagy in gastrointestinal cancers Biochim. Biophys. Acta, Mol. Basis Dis. 2022 166512
13 Behrouj H. Vakili O. Sadeghdoust A. Aligolighasemabadi N. Khalili P. Zamani M. Mokarram P. Epigenetic regulation of autophagy in coronavirus disease 2019 (COVID-19) Biochemistry and Biophysics Reports 30 2022 101264
14 Li X. He S. Ma B. Autophagy and autophagy-related proteins in cancer Mol. Cancer 19 1 2020 1 16 31901224
15 Pro-survival autophagy: an emerging candidate of tumor progression through maintaining hallmarks of cancer Das C.K. Banerjee I. Mandal M. Seminars in Cancer Biology 2020 Elsevier
16 Mele L. Del Vecchio V. Liccardo D. Prisco C. Schwerdtfeger M. Robinson N. The role of autophagy in resistance to targeted therapies Cancer Treat Rev. 88 2020 102043
17 Akkoc Y. Peker N. Akcay A. Gozuacik D. Autophagy and cancer dormancy Front. Oncol. 11 2021 627023
18 Zalpoor H. Bakhtiyari M. Akbari A. Aziziyan F. Shapourian H. Liaghat M. Potential role of autophagy induced by FLT3-ITD and acid ceramidase in acute myeloid leukemia chemo-resistance: new insights Cell Commun. Signal. 20 1 2022 172 36316776
19 Lao Y. Shen D. Zhang W. He R. Jiang M. Immune checkpoint inhibitors in cancer therapy—how to overcome drug resistance? Cancers 14 15 2022 3575 35892835
20 Park Y.-J. Kuen D.-S. Chung Y. Future prospects of immune checkpoint blockade in cancer: from response prediction to overcoming resistance Exp. Mol. Med. 50 8 2018 1 13
21 Oncogenic signaling pathways associated with immune evasion and resistance to immune checkpoint inhibitors in cancer Kobayashi Y. Lim S.-O. Yamaguchi H. Seminars in Cancer Biology 2020 Elsevier
22 Ottaviano M. De Placido S. Ascierto P.A. Recent success and limitations of immune checkpoint inhibitors for cancer: a lesson from melanoma Virchows Arch. 474 2019 421 432 30747264
23 Marin-Acevedo J.A. Kimbrough E.O. Lou Y. Next generation of immune checkpoint inhibitors and beyond J. Hematol. Oncol. 14 1 2021 1 29 33402199
24 Cancer and the immune system: the history and background of immunotherapy Abbott M. Ustoyev Y. Seminars in Oncology Nursing 2019 Elsevier
25 Wu B. Shi X. Jiang M. Liu H. Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment Mol. Cancer 22 1 2023 1 22 36597126
26 Han Y. Liu D. Li L. PD-1/PD-L1 pathway: current researches in cancer Am. J. Cancer Res. 10 3 2020 727 32266087
27 Ai L. Xu A. Xu J. Roles of PD-1/PD-L1 pathway: signaling, cancer, and beyond Regulation of Cancer Immune Checkpoints: Molecular and Cellular Mechanisms and Therapy 2020 33 59
28 Salmaninejad A. Valilou S.F. Shabgah A.G. Aslani S. Alimardani M. Pasdar A. Sahebkar A. PD‐1/PD‐L1 pathway: basic biology and role in cancer immunotherapy J. Cell. Physiol. 234 10 2019 16824 16837 30784085
29 Zhang H. Dai Z. Wu W. Wang Z. Zhang N. Zhang L. Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer J. Exp. Clin. Cancer Res. 40 1 2021 1 22 33390177
30 Sobhani N. Tardiel-Cyril D.R. Davtyan A. Generali D. Roudi R. Li Y. CTLA-4 in regulatory T cells for cancer immunotherapy Cancers 13 6 2021 1440 33809974
31 Fares C.M. Van Allen E.M. Drake C.G. Allison J.P. Hu-Lieskovan S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? American Society of Clinical Oncology Educational Book 39 2019 147 164 31099674
32 Schoenfeld A.J. Hellmann M.D. Acquired resistance to immune checkpoint inhibitors Cancer Cell 37 4 2020 443 455 32289269
33 Walsh R.J. Soo R.A. Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies Therapeutic advances in medical oncology 12 2020 1758835920937902
34 Vukadin S. Khaznadar F. Kizivat T. Vcev A. Smolic M. Molecular mechanisms of resistance to immune checkpoint inhibitors in melanoma treatment: an update Biomedicines 9 7 2021 835 34356899
35 Jiang G.-M. Tan Y. Wang H. Peng L. Chen H.-T. Meng X.-J. The relationship between autophagy and the immune system and its applications for tumor immunotherapy Mol. Cancer 18 2019 1 22 30609930
36 Thorburn A. Towers C.G. Enhancing anti-tumor immunity by autophagy inhibition Nature Cancer 2 5 2021 484 486 35122020
37 Onorati A.V. Dyczynski M. Ojha R. Amaravadi R.K. Targeting autophagy in cancer Cancer 124 16 2018 3307 3318 29671878
38 Amaravadi R.K. Kimmelman A.C. Debnath J. Targeting autophagy in cancer: recent advances and future DirectionsTargeting autophagy in cancer Cancer Discov. 9 9 2019 1167 1181 31434711
39 Bishop E. Bradshaw T.D. Autophagy modulation: a prudent approach in cancer treatment? Cancer Chemother. Pharmacol. 82 2018 913 922 30182146
40 Qiao Y. Choi J.E. Tien J.C. Simko S.A. Rajendiran T. Vo J.N. Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer Nature cancer 2 9 2021 978 993 34738088
41 Russell R.C. Guan K.L. The multifaceted role of autophagy in cancer EMBO J. 41 13 2022 e110031
42 Jain V. Singh M.P. Amaravadi R.K. Recent advances in targeting autophagy in cancer Trends Pharmacol. Sci. 44 5 2023 290 302 36931971
43 Dikic I. Elazar Z. Mechanism and medical implications of mammalian autophagy Nat. Rev. Mol. Cell Biol. 19 6 2018 349 364 29618831
44 Dashti Z. Yousefi Z. Kiani P. Taghizadeh M. Maleki M.H. Borji M. Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth Metabolism 2024 155811
45 Ghavami S. Zamani M. Ahmadi M. Erfani M. Dastghaib S. Darbandi M. Epigenetic regulation of autophagy in gastrointestinal cancers Biochim. Biophys. Acta, Mol. Basis Dis. 1868 11 2022 166512
46 Vakili O. Borji M. Saffari-Chaleshtori J. Shafiee S.M. Ameliorative effects of bilirubin on cell culture model of non-alcoholic fatty liver disease Mol. Biol. Rep. 50 5 2023 4411 4422 36971910
47 Reggiori F. Ungermann C. Autophagosome maturation and fusion J. Mol. Biol. 429 4 2017 486 496 28077293
48 Al‐Bari M.A.A. Xu P. Molecular regulation of autophagy machinery by mTOR‐dependent and‐independent pathways Ann. N. Y. Acad. Sci. 1467 1 2020 3 20 31985829
49 Ichimiya T. Yamakawa T. Hirano T. Yokoyama Y. Hayashi Y. Hirayama D. Autophagy and autophagy-related diseases: a review Int. J. Mol. Sci. 21 23 2020 8974 33255983
50 Lamark T. Johansen T. Mechanisms of selective autophagy Annu. Rev. Cell Dev. Biol. 37 2021 143 169 34152791
51 Hernández-Cáceres M.P. Munoz L. Pradenas J.M. Pena F. Lagos P. Aceiton P. Mechanobiology of autophagy: the unexplored side of cancer Front. Oncol. 11 2021 632956
52 Yang Y. Zheng L. Zheng X. Ge L. Autophagosomal membrane origin and formation Autophagy: Biology and Diseases: Technology and Methodology 2021 17 42
53 Xu Z. Han X. Ou D. Liu T. Li Z. Jiang G. Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy Appl. Microbiol. Biotechnol. 104 2020 575 587 31832711
54 Mizushima N. The ATG conjugation systems in autophagy Curr. Opin. Cell Biol. 63 2020 1 10 31901645
55 Ueno T. Komatsu M. Monitoring autophagy flux and activity: principles and applications Bioessays 42 11 2020 2000122
56 You Z. Xu Y. Wan W. Zhou L. Li J. Zhou T. TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction Autophagy 15 8 2019 1309 1321 30767704
57 Fan S. Yue L. Wan W. Zhang Y. Zhang B. Otomo C. Inhibition of autophagy by a small molecule through covalent modification of the LC3 protein Angew. Chem. Int. Ed. 60 50 2021 26105 26114
58 Wen X. Klionsky D.J. At a Glance: A History of Autophagy and Cancer. Seminars in Cancer Biology 2020 Elsevier
59 Fujioka Y. Alam J.M. Noshiro D. Mouri K. Ando T. Okada Y. Phase separation organizes the site of autophagosome formation Nature 578 7794 2020 301 305 32025038
60 Mahapatra K.K. Panigrahi D.P. Praharaj P.P. Bhol C.S. Patra S. Mishra S.R. Molecular interplay of autophagy and endocytosis in human health and diseases Biol. Rev. 94 4 2019 1576 1590 30989802
61 Button R.W. Roberts S.L. Willis T.L. Hanemann C.O. Luo S. Accumulation of autophagosomes confers cytotoxicity J. Biol. Chem. 292 33 2017 13599 13614 28673965
62 Kuchitsu Y. Fukuda M. Revisiting Rab7 functions in mammalian autophagy: Rab7 knockout studies Cells 7 11 2018 215 30463228
63 Stroupe C. This is the end: regulation of Rab7 nucleotide binding in endolysosomal trafficking and autophagy Front. Cell Dev. Biol. 6 2018 129 30333976
64 Nakamura S. Yoshimori T. New insights into autophagosome–lysosome fusion J. Cell Sci. 130 7 2017 1209 1216 28302910
65 Das C.K. Mandal M. Kögel D. Pro-survival autophagy and cancer cell resistance to therapy Cancer Metastasis Rev. 37 2018 749 766 29536228
66 Kageyama S. Gudmundsson S.R. Sou Y.-S. Ichimura Y. Tamura N. Kazuno S. p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response Nat. Commun. 12 1 2021 16 33397898
67 Vitto V.A.M. Bianchin S. Zolondick A.A. Pellielo G. Rimessi A. Chianese D. Molecular mechanisms of autophagy in cancer development, progression, and therapy Biomedicines 10 7 2022 1596 35884904
68 Patergnani S. Missiroli S. Morciano G. Perrone M. Mantovani C.M. Anania G. Understanding the role of autophagy in cancer formation and progression is a real opportunity to treat and cure human cancers Cancers 13 22 2021 5622 34830777
69 Dorostgou Z. Yadegar N. Dorostgou Z. Khorvash F. Vakili O. Novel insights into the role of circular RNAs in Parkinson disease: an emerging renaissance in the management of neurodegenerative diseases J. Neurosci. Res. 100 9 2022 1775 1790 35642104
70 Napoletano F. Baron O. Vandenabeele P. Mollereau B. Fanto M. Intersections between regulated cell death and autophagy Trends Cell Biol. 29 4 2019 323 338 30665736
71 Liu J. Hong M. Li Y. Chen D. Wu Y. Hu Y. Programmed cell death tunes tumor immunity Front. Immunol. 13 2022 1196
72 Verma A.K. Bharti P.S. Rafat S. Bhatt D. Goyal Y. Pandey K.K. Autophagy paradox of cancer: role, regulation, and duality Oxid. Med. Cell. Longev. 2021 2021
73 Gewirtz D.A. The four faces of autophagy: implications for cancer TherapyAutophagy and cancer therapy Cancer Res. 74 3 2014 647 651 24459182
74 Comel A. Sorrentino G. Capaci V. Del Sal G. The cytoplasmic side of p53's oncosuppressive activities FEBS Lett. 588 16 2014 2600 2609 24747877
75 Yun C.W. Lee S.H. The roles of autophagy in cancer Int. J. Mol. Sci. 19 11 2018 3466 30400561
76 Shorning B.Y. Dass M.S. Smalley M.J. Pearson H.B. The PI3K-AKT-mTOR pathway and prostate cancer: at the crossroads of AR, MAPK, and WNT signaling Int. J. Mol. Sci. 21 12 2020 4507 32630372
77 Movahedpour A. Vakili O. Khalifeh M. Mousavi P. Mahmoodzadeh A. Taheri‐Anganeh M. Mammalian target of rapamycin (mTOR) signaling pathway and traumatic brain injury: a novel insight into targeted therapy Cell Biochem. Funct. 40 3 2022 232 247 35258097
78 Gil J. Ramsey D. Szmida E. Leszczynski P. Pawlowski P. Bebenek M. Sasiadek M.M. The BAX gene as a candidate for negative autophagy-related genes regulator on mRNA levels in colorectal cancer Med. Oncol. 34 2017 1 7 27889880
79 Mohammadi K. Salimi M. Angaji S.A. Saniotis A. Mahjoobi F. Association study of Bif-1 gene expression with histopathological characteristics and hormone receptors in breast cancer BMC Wom. Health 22 1 2022 471
80 Song Y. Quach C. Liang C. UVRAG in autophagy, inflammation, and cancer Autophagy 16 2 2020 387 388 31905312
81 Looi C.-K. Hii L.-W. Ngai S.C. Leong C.-O. Mai C.-W. The role of Ras-associated protein 1 (Rap1) in cancer: bad actor or good player? Biomedicines 8 9 2020 334 32906721
82 Poillet-Perez L. Sarry J.-E. Joffre C. Autophagy is a major metabolic regulator involved in cancer therapy resistance Cell Rep. 36 7 2021 109528
83 Chang H. Zou Z. Targeting autophagy to overcome drug resistance: further developments J. Hematol. Oncol. 13 1 2020 159 33239065
84 Ravanan P. Srikumar I.F. Talwar P. Autophagy: the spotlight for cellular stress responses Life Sci. 188 2017 53 67 28866100
85 Sui X. Chen R. Wang Z. Huang Z. Kong N. Zhang M. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment Cell Death Dis. 4 10 2013 e838 e 24113172
86 Liu F. Ai F.Y. Zhang D.C. Tian L. Yang Z.Y. Liu S.J. LncRNA NEAT1 knockdown attenuates autophagy to elevate 5‐FU sensitivity in colorectal cancer via targeting miR‐34a Cancer Med. 9 3 2020 1079 1091 31802650
87 Herbener V.J. Burster T. Goreth A. Pruss M. von Bandemer H. Baisch T. Considering the experimental use of temozolomide in glioblastoma research Biomedicines 8 6 2020 151 32512726
88 Singh N. Miner A. Hennis L. Mittal S. Mechanisms of temozolomide resistance in glioblastoma-a comprehensive review Cancer drug resistance 4 1 2021 17 43 34337348
89 Gao L. Zheng H. Cai Q. Wei L. Autophagy and tumour radiotherapy. Autophagy: biology and diseases Clin. Sci. 2020 375 387
90 Niu J. Yan T. Guo W. Wang W. Zhao Z. Insight into the role of autophagy in osteosarcoma and its therapeutic implication Front. Oncol. 9 2019 1232 31803616
91 Schötz U. Balzer V. Brandt F.-W. Ziemann F. Subtil F.S. Rieckmann T. Dual PI3K/mTOR inhibitor NVP-BEZ235 enhances radiosensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines due to suppressed double-strand break (DSB) repair by non-homologous end joining Cancers 12 2 2020 467 32085396
92 Schulz A. Meyer F. Dubrovska A. Borgmann K. Cancer stem cells and radioresistance: DNA repair and beyond Cancers 11 6 2019 862 31234336
93 Arnold C.R. Mangesius J. Skvortsova I.-I. Ganswindt U. The role of cancer stem cells in radiation resistance Front. Oncol. 10 2020 164 32154167
94 Najafi M. Mortezaee K. Majidpoor J. Cancer stem cell (CSC) resistance drivers Life Sci. 234 2019 116781
95 Sanati M. Binabaj M.M. Ahmadi S.S. Aminyavari S. Javid H. Mollazadeh H. Recent advances in glioblastoma multiforme therapy: a focus on autophagy regulation Biomed. Pharmacother. 155 2022 113740
96 Brunel A. Hombourger S. Barthout E. Battu S. Kögel D. Antonietti P. Autophagy inhibition reinforces stemness together with exit from dormancy of polydisperse glioblastoma stem cells Aging (Albany NY) 13 14 2021 18106
97 Li L. Liu W.-L. Su L. Lu Z-c He X-s The role of autophagy in cancer radiotherapy Curr. Mol. Pharmacol. 13 1 2020 31 40 31400274
98 Yuan X. Du J. Hua S. Zhang H. Gu C. Wang J. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells Exp. Cell Res. 330 2 2015 267 276 25220423
99 Chen Y. Song H. Lu Y. Li X. Chen T. Zhang Y. Autophagy inhibition contributes to radiation sensitization of esophageal squamous carcinoma cells Dis. Esophagus 24 6 2011 437 443 21166739
100 Rahman M.A. Islam F. Hasan M. Joya I.S. Mithila M.M. Islam M.F. Rahman M.R. Monoclonal antibody: a cell specific immunotherapy to treat cancer Int. J. Basic Clin. Pharmacol. 12 2 2023 290
101 Monoclonal antibodies for the treatment of cancer Shuptrine C.W. Surana R. Weiner L.M. Seminars in Cancer Biology 2012 Elsevier
102 Guo X-l Li D. Sun K. Wang J. Liu Y. Song J-r Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma J. Mol. Med. 91 2013 473 483 23052483
103 Zambrano J. Yeh E.S. Autophagy and apoptotic crosstalk: mechanism of therapeutic resistance in HER2-positive breast cancer Breast Cancer Basic Clin. Res. 10 2016 BCBCR. S32791
104 Li Y-y Lam S-k Mak JC-w Zheng C-y Ho JC-m Erlotinib-induced autophagy in epidermal growth factor receptor mutated non-small cell lung cancer Lung Cancer 81 3 2013 354 361 23769318
105 Yamaguchi H. Hsu J.-M. Yang W.-H. Hung M.-C. Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics Nat. Rev. Clin. Oncol. 19 5 2022 287 305 35132224
106 Zhai B. Hu F. Jiang X. Xu J. Zhao D. Liu B. Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular CarcinomaAkt/autophagy for sorafenib resistance in HCC Mol. Cancer Therapeut. 13 6 2014 1589 1598
107 Nagelkerke A. Sieuwerts A.M. Bussink J. Sweep F. Look M.P. Foekens J.A. LAMP3 is involved in tamoxifen resistance in breast cancer cells through the modulation of autophagy Endocr. Relat. Cancer 21 1 2014 101 112 24434718
108 Zhang Y. Zheng J. Functions of immune checkpoint molecules beyond immune evasion Regulation of Cancer Immune Checkpoints: Molecular and Cellular Mechanisms and Therapy 2020 201 226
109 D'Arrigo P. Tufano M. Rea A. Vigorito V. Novizio N. Russo S. Manipulation of the immune system for cancer defeat: a focus on the T cell inhibitory checkpoint molecules Curr. Med. Chem. 27 15 2020 2402 2448 30398102
110 Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy Nat. Rev. Cancer 12 4 2012 252 264 22437870
111 Reisländer T. Groelly F.J. Tarsounas M. DNA damage and cancer immunotherapy: a STING in the tale Mol. Cell 80 1 2020 21 28 32810436
112 Amodio V. Mauri G. Reilly N.M. Sartore-Bianchi A. Siena S. Bardelli A. Germano G. Mechanisms of immune escape and resistance to checkpoint inhibitor therapies in mismatch repair deficient metastatic colorectal cancers Cancers 13 11 2021 2638 34072037
113 Mortezaee K. Immune escape: a critical hallmark in solid tumors Life Sci. 258 2020 118110
114 Montesion M. Murugesan K. Jin D.X. Sharaf R. Sanchez N. Guria A. Somatic HLA class I loss is a widespread mechanism of immune evasion which refines the use of tumor mutational burden as a biomarker of checkpoint inhibitor ResponsePan-cancer analysis of HLA LOH as a method of immune evasion Cancer Discov. 11 2 2021 282 292 33127846
115 Taghiloo S. Asgarian-Omran H. Immune evasion mechanisms in acute myeloid leukemia: a focus on immune checkpoint pathways Crit. Rev. Oncol. Hematol. 157 2021 103164
116 Vinay D.S. Ryan E.P. Pawelec G. Talib W.H. Stagg J. Elkord E. Immune Evasion in Cancer: Mechanistic Basis and Therapeutic Strategies. Seminars in Cancer Biology 2015 Elsevier
117 Shiravand Y. Khodadadi F. Kashani S.M.A. Hosseini-Fard S.R. Hosseini S. Sadeghirad H. Immune checkpoint inhibitors in cancer therapy Curr. Oncol. 29 5 2022 3044 3060 35621637
118 Das S. Johnson D.B. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors Journal for immunotherapy of cancer 7 1 2019 1 11 30612589
119 Naimi A. Mohammed R.N. Raji A. Chupradit S. Yumashev A.V. Suksatan W. Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons Cell Commun. Signal. 20 1 2022 1 31 34980146
120 Bagchi S. Yuan R. Engleman E.G. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance Annu. Rev. Pathol. 16 2021 223 249 33197221
121 He X. Xu C. Immune checkpoint signaling and cancer immunotherapy Cell Res. 30 8 2020 660 669 32467592
122 Wei S.C. Duffy C.R. Allison J.P. Fundamental mechanisms of immune checkpoint blockade TherapyFundamental mechanisms of immune checkpoint blockade therapy Cancer Discov. 8 9 2018 1069 1086 30115704
123 Van Coillie S. Wiernicki B. Xu J. Molecular and cellular functions of CTLA-4 Regulation of Cancer Immune Checkpoints: Molecular and Cellular Mechanisms and Therapy 2020 7 32
124 Seidel J.A. Otsuka A. Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations Front. Oncol. 8 2018 86 29644214
125 Rohaan M.W. Borch T.H. van den Berg J.H. Met Ö. Kessels R. Geukes Foppen M.H. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma N. Engl. J. Med. 387 23 2022 2113 2125 36477031
126 Hamanishi J. Mandai M. Matsumura N. Abiko K. Baba T. Konishi I. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues Int. J. Clin. Oncol. 21 2016 462 473 26899259
127 Boustani J. Lecoester B. Baude J. Latour C. Adotevi O. Mirjolet C. Truc G. Anti-PD-1/Anti-PD-l1 drugs and radiation therapy: combinations and optimization strategies Cancers 13 19 2021 4893 34638376
128 Robert C. A decade of immune-checkpoint inhibitors in cancer therapy Nat. Commun. 11 1 2020 3801 32732879
129 Darvin P. Toor S.M. Sasidharan Nair V. Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers Exp. Mol. Med. 50 12 2018 1 11
130 Jenkins R.W. Barbie D.A. Flaherty K.T. Mechanisms of resistance to immune checkpoint inhibitors British journal of cancer 118 1 2018 9 16 29319049
131 Pitt J.M. Vétizou M. Daillère R. Roberti M.P. Yamazaki T. Routy B. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and-extrinsic factors Immunity 44 6 2016 1255 1269 27332730
132 Restifo N.P. Smyth M.J. Snyder A. Acquired resistance to immunotherapy and future challenges Nat. Rev. Cancer 16 2 2016 121 126 26822578
133 O'Donnell J.S. Long G.V. Scolyer R.A. Teng M.W. Smyth M.J. Resistance to PD1/PDL1 checkpoint inhibition Cancer Treat Rev. 52 2017 71 81 27951441
134 Sharma P. Hu-Lieskovan S. Wargo J.A. Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy Cell 168 4 2017 707 723 28187290
135 Marin-Acevedo J.A. Chirila R.M. Dronca R.S. Immune Checkpoint Inhibitor Toxicities. Mayo Clinic Proceedings 2019 Elsevier
136 Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade N. Engl. J. Med. 378 2 2018 158 168 29320654
137 Granier C. De Guillebon E. Blanc C. Roussel H. Badoual C. Colin E. Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer ESMO open 2 2 2017 e000213
138 Marin-Acevedo J.A. Dholaria B. Soyano A.E. Knutson K.L. Chumsri S. Lou Y. Next generation of immune checkpoint therapy in cancer: new developments and challenges J. Hematol. Oncol. 11 2018 1 20 29298689
139 Levy J.M.M. Towers C.G. Thorburn A. Targeting autophagy in cancer Nat. Rev. Cancer 17 9 2017 528 542 28751651
140 Noman M.Z. Parpal S. Van Moer K. Xiao M. Yu Y. Arakelian T. Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti–PD-1/PD-L1 immunotherapy Sci. Adv. 6 18 2020 eaax7881
141 Yamamoto K. Venida A. Yano J. Biancur D.E. Kakiuchi M. Gupta S. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I Nature 581 7806 2020 100 105 32376951
142 Keller C.W. Loi M. Ligeon L.A. Gannagé M. Lünemann J.D. Münz C. Endocytosis regulation by autophagy proteins in MHC restricted antigen presentation Curr. Opin. Immunol. 52 2018 68 73 29719275
143 Loi M. Ligeon L.A. Münz C. MHC class I internalization via autophagy proteins Methods Mol. Biol. 1880 2019 455 477 30610715
144 Baghdadi M. Yoneda A. Yamashina T. Nagao H. Komohara Y. Nagai S. TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance Immunity 39 6 2013 1070 1081 24315994
145 Yi Y. Zhou Z. Shu S. Fang Y. Twitty C. Hilton T.L. Autophagy-assisted antigen cross-presentation: autophagosome as the argo of shared tumor-specific antigens and DAMPs OncoImmunology 1 6 2012 976 978 23162777
146 Fan J. Wu Y. Jiang M. Wang L. Yin D. Zhang Y. IFN-DC loaded with autophagosomes containing virus antigen is highly efficient in inducing virus-specific human T cells Int. J. Med. Sci. 16 5 2019 741 750 31217742
147 Xing Y. Cao R. Hu H.M. TLR and NLRP3 inflammasome-dependent innate immune responses to tumor-derived autophagosomes (DRibbles) Cell Death Dis. 7 8 2016 e2322 27490927
148 Li Y. Wang L.X. Pang P. Cui Z. Aung S. Haley D. Tumor-derived autophagosome vaccine: mechanism of cross-presentation and therapeutic efficacy Clin. Cancer Res. 17 22 2011 7047 7057 22068657
149 Jin M. Zhang Y. Autophagy and inflammatory diseases Adv. Exp. Med. Biol. 1207 2020 391 400 32671761
150 Rao L. Eissa N.T. Autophagy in pulmonary innate immunity J. Innate Immun. 12 1 2020 21 30 31018206
151 Yamamoto K. Venida A. Yano J. Biancur D.E. Kakiuchi M. Gupta S. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I Nature 581 7806 2020 100 105 32376951
152 Cheung P.F. Yang J. Fang R. Borgers A. Krengel K. Stoffel A. Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression Nat. Commun. 13 1 2022 156 35013174
153 Hindson J. PDAC resistance to immunotherapy - a role for autophagy? Nat. Rev. Gastroenterol. Hepatol. 17 7 2020 382
154 Noman M.Z. Parpal S. Van Moer K. Xiao M. Yu Y. Viklund J. Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti-PD-1/PD-L1 immunotherapy Sci. Adv. 6 18 2020 eaax7881
155 Palomino D.C. Marti L.C. Chemokines and immunity Einstein (Sao Paulo) 13 3 2015 469 473 26466066
156 Deng J. Thennavan A. Dolgalev I. Chen T. Li J. Marzio A. ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1 mutant lung cancer Nat Cancer 2 5 2021 503 514 34142094
157 Lawson K.A. Sousa C.M. Zhang X. Kim E. Akthar R. Caumanns J.J. Functional genomic landscape of cancer-intrinsic evasion of killing by T cells Nature 586 7827 2020 120 126 32968282
158 Kearney C.J. Vervoort S.J. Hogg S.J. Ramsbottom K.M. Freeman A.J. Lalaoui N. Tumor immune evasion arises through loss of TNF sensitivity Sci Immunol. 3 23 2018
159 Chen A.Y. Wolchok J.D. Bass A.R. TNF in the era of immune checkpoint inhibitors: friend or foe? Nat. Rev. Rheumatol. 17 4 2021 213 223 33686279
160 Ramakrishnan R. Gabrilovich D.I. The role of mannose-6-phosphate receptor and autophagy in influencing the outcome of combination therapy Autophagy 9 4 2013 615 616 23324210
161 Chollat-Namy M. Ben Safta-Saadoun T. Haferssas D. Meurice G. Chouaib S. Thiery J. The pharmalogical reactivation of p53 function improves breast tumor cell lysis by granzyme B and NK cells through induction of autophagy Cell Death Dis. 10 10 2019 695 31541080
162 Zamame Ramirez J.A. Romagnoli G.G. Falasco B.F. Gorgulho C.M. Sanzochi Fogolin C. Dos Santos D.C. Blocking drug-induced autophagy with chloroquine in HCT-116 colon cancer cells enhances DC maturation and T cell responses induced by tumor cell lysate Int Immunopharmacol 84 2020 106495
163 Akalay I. Janji B. Hasmim M. Noman M.Z. André F. De Cremoux P. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis Cancer Res. 73 8 2013 2418 2427 23436798
164 von Roemeling C.A. Wang Y. Qie Y. Yuan H. Zhao H. Liu X. Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity Nat. Commun. 11 1 2020 1508 32198351
165 Shi C.S. Shenderov K. Huang N.N. Kabat J. Abu-Asab M. Fitzgerald K.A. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction Nat. Immunol. 13 3 2012 255 263 22286270
166 Peral de Castro C. Jones S.A. C N.C. Hearnden C.A. Williams L. Winter J. Autophagy regulates IL-23 secretion and innate T cell responses through effects on IL-1 secretion J. Immunol. 189 8 2012 4144 4153 22972933
167 Nambu A. Nakae S. Iwakura Y. IL-1beta, but not IL-1alpha, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses Int. Immunol. 18 5 2006 701 712 16569679
168 Lotze M.T. Buchser W. Liang X. Blocking the interleukin 2 (IL2)-induced systemic autophagic syndrome promotes profound antitumor effects and limits toxicity Autophagy 8 8 2012 1264 1266 22660171
169 Mgrditchian T. Arakelian T. Paggetti J. Noman M.Z. Viry E. Moussay E. Targeting autophagy inhibits melanoma growth by enhancing NK cells infiltration in a CCL5-dependent manner Proc. Natl. Acad. Sci. USA 114 44 2017 E9271 E9279 29078276
170 Viry E. Baginska J. Berchem G. Noman M.Z. Medves S. Chouaib S. Janji B. Autophagic degradation of GZMB/granzyme B: a new mechanism of hypoxic tumor cell escape from natural killer cell-mediated lysis Autophagy 10 1 2014 173 175 24248158
171 Fridman W.H. Pagès F. Sautès-Fridman C. Galon J. The immune contexture in human tumours: impact on clinical outcome Nat. Rev. Cancer 12 4 2012 298 306 22419253
172 Carreras J. Kikuti Y.Y. Miyaoka M. Hiraiwa S. Tomita S. Ikoma H. A Combination of Multilayer Perceptron, Radial Basis Function Artificial Neural Networks and Machine Learning Image Segmentation for the Dimension Reduction and the Prognosis Assessment of Diffuse Large B-Cell Lymphoma. Ai 2021 106 134 2(1
173 Tang T. Huang X. Zhang G. Hong Z. Bai X. Liang T. Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy Signal Transduct. Targeted Ther. 6 1 2021 72
174 Binnewies M. Roberts E.W. Kersten K. Chan V. Fearon D.F. Merad M. Understanding the tumor immune microenvironment (TIME) for effective therapy Nat. Med. 24 5 2018 541 550 29686425
175 Zhang Y. Chen L. Classification of advanced human cancers based on tumor immunity in the microenvironment (TIME) for cancer immunotherapy JAMA Oncol. 2 11 2016 1403 1404 27490017
176 Petitprez F. Meylan M. de Reyniès A. Sautès-Fridman C. Fridman W.H. The tumor microenvironment in the response to immune checkpoint blockade therapies Front. Immunol. 11 2020 784 32457745
177 Yoshihama S. Roszik J. Downs I. Meissner T.B. Vijayan S. Chapuy B. NLRC5/MHC class I transactivator is a target for immune evasion in cancer Proc. Natl. Acad. Sci. USA 113 21 2016 5999 6004 27162338
178 Mojic M. Takeda K. Hayakawa Y. The dark side of IFN-γ: its role in promoting cancer immunoevasion Int. J. Mol. Sci. 19 1 2017 89 29283429
179 Khong H.T. Restifo N.P. Natural selection of tumor variants in the generation of “tumor escape” phenotypes Nat. Immunol. 3 11 2002 999 1005 12407407
180 Bestion E. Raymond E. Mezouar S. Halfon P. Update on autophagy inhibitors in cancer: opening up to a therapeutic combination with immune checkpoint inhibitors Cells 12 13 2023 1702 37443736
181 Chen D.S. Mellman I. Elements of cancer immunity and the cancer–immune set point Nature 541 7637 2017 321 330 28102259
182 Wolchok J. Putting the immunologic brakes on cancer Cell 175 6 2018 1452 1454 30500529
183 O'Reilly E.M. Oh D.-Y. Dhani N. Renouf D.J. Lee M.A. Sun W. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial JAMA Oncol. 5 10 2019 1431 1438 31318392
184 Xiao Y. Yu D. Tumor microenvironment as a therapeutic target in cancer Pharmacol. Ther. 221 2021 107753
185 Baghban R. Roshangar L. Jahanban-Esfahlan R. Seidi K. Ebrahimi-Kalan A. Jaymand M. Tumor microenvironment complexity and therapeutic implications at a glance Cell Commun. Signal. 18 2020 1 19 31900175
186 Duan Z. Luo Y. Targeting macrophages in cancer immunotherapy Signal Transduct. Targeted Ther. 6 1 2021 127
187 Jang Y.J. Kim J.H. Byun S. Modulation of autophagy for controlling immunity Cells 8 2 2019 138 30744138
188 Maes H. Rubio N. Garg A.D. Agostinis P. Autophagy: shaping the tumor microenvironment and therapeutic response Trends Mol. Med. 19 7 2013 428 446 23714574
189 Amaravadi R.K. Lippincott-Schwartz J. Yin X.-M. Weiss W.A. Takebe N. Timmer W. Principles and current strategies for targeting autophagy for cancer treatment Clin. Cancer Res. 17 4 2011 654 666 21325294
190 Liang X. De Vera M.E. Buchser W.J. de Vivar Chavez A.R. Loughran P. Stolz D.B. Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression Cancer Res. 72 11 2012 2791 2801 22472122
191 Wang H. Yao H. Li C. Shi H. Lan J. Li Z. HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity Nat. Chem. Biol. 15 1 2019 42 50 30397328
192 Sharma G. Ojha R. Noguera-Ortega E. Rebecca V.W. Attanasio J. Liu S. PPT1 inhibition enhances the antitumor activity of anti–PD-1 antibody in melanoma JCI insight 5 17 2020
193 Ou P. Wen L. Liu X. Huang J. Huang X. Su C. Thioesterase PPT1 balances viral resistance and efficient T cell crosspriming in dendritic cells J. Exp. Med. 216 9 2019 2091 2112 31262842
194 Chen D. Xie J. Fiskesund R. Dong W. Liang X. Lv J. Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype Nat. Commun. 9 1 2018 873 29491374
195 Maycotte P. Jones K.L. Goodall M.L. Thorburn J. Thorburn A. Autophagy supports breast cancer stem cell maintenance by regulating IL6 secretionautophagy regulates IL6 secretion and breast cancer stem cells Mol. Cancer Res. 13 4 2015 651 658 25573951
196 Cominetti M.R. Terruggi C.H. Ramos O.H. Fox J.W. Mariano-Oliveira A. De Freitas M.S. Alternagin-C, a disintegrin-like protein, induces vascular endothelial cell growth factor (VEGF) expression and endothelial cell proliferation in vitro J. Biol. Chem. 279 18 2004 18247 18255 14766757
197 Sung S.J. Kim H.-K. Hong Y.-K. Joe Y.A. Autophagy is a potential target for enhancing the anti-angiogenic effect of mebendazole in endothelial cells Biomolecules & Therapeutics 27 1 2019 117 30642153
198 Chen R.Q. Xu X.H. Liu F. Li C.Y. Li Y.J. Li X.R. The binding of PD-L1 and Akt facilitates glioma cell invasion upon starvation via Akt/Autophagy/F-Actin signaling Front. Oncol. 9 2019 1347 31850228
199 Liang J. Wang L. Wang C. Shen J. Su B. Marisetty A.L. Verteporfin inhibits PD-L1 through autophagy and the STAT1–IRF1–TRIM28 signaling Axis, exerting antitumor EfficacyVerteporfin inhibits PD-L1 Cancer Immunol. Res. 8 7 2020 952 965 32265228
200 Gao L. Chen Y. Autophagy controls programmed death-ligand 1 expression on cancer cells Biomedical Reports 15 4 2021 1 9
201 Gao Z. Chen J.-F. Li X.-G. Shi Y.-H. Tang Z. Liu W.-R. KRAS acting through ERK signaling stabilizes PD-L1 via inhibiting autophagy pathway in intrahepatic cholangiocarcinoma Cancer Cell Int. 22 1 2022 1 12 34980127
202 Andrea A.E. Chiron A. Mallah S. Bessoles S. Sarrabayrouse G. Hacein-Bey-Abina S. Advances in CAR-T cell genetic engineering strategies to overcome hurdles in solid tumors treatment Front. Immunol. 2022 309
203 Wu J. Zhao X. Sun Q. Jiang Y. Zhang W. Luo J. Li Y. Synergic effect of PD-1 blockade and endostar on the PI3K/AKT/mTOR-mediated autophagy and angiogenesis in Lewis lung carcinoma mouse model Biomed. Pharmacother. 125 2020 109746
204 Rudnick J.A. Monkkonen T. Mar F.A. Barnes J.M. Starobinets H. Goldsmith J. Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis Gene Dev. 35 13–14 2021 963 975 34168038
205 Yuwen D. Mi S. Ma Y. Guo W. Xu Q. Shen Y. Shu Y. Andrographolide enhances cisplatin-mediated anticancer effects in lung cancer cells through blockade of autophagy Anti Cancer Drugs 28 9 2017 967 976 28692436
206 Tang D. Zhao D. Wu Y. Yao R. Zhou L. Lu L. The miR‐3127‐5p/p‐STAT 3 axis up‐regulates PD‐L1 inducing chemoresistance in non‐small‐cell lung cancer J. Cell Mol. Med. 22 8 2018 3847 3856 29726585
207 Cao P. Yang X. Liu D. Ye S. Yang W. Xie Z. Lei X. Research progress of PD‐L1 non‐glycosylation in cancer immunotherapy Scand. J. Immunol. 96 4 2022 e13205
208 Gou Q. Dong C. Xu H. Khan B. Jin J. Liu Q. PD-L1 degradation pathway and immunotherapy for cancer Cell Death Dis. 11 11 2020 955 33159034
209 Duan Y. Tian X. Liu Q. Jin J. Shi J. Hou Y. Role of autophagy on cancer immune escape Cell Commun. Signal. 19 2021 1 12 33397378
210 Martin A.M. Nirschl T.R. Nirschl C.J. Francica B.J. Kochel C.M. van Bokhoven A. Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance Prostate Cancer Prostatic Dis. 18 4 2015 325 332 26260996
211 Wang M. Wisniewski C.A. Xiong C. Chhoy P. Goel H.L. Kumar A. Therapeutic blocking of VEGF binding to neuropilin-2 diminishes PD-L1 expression to activate antitumor immunity in prostate cancer Sci. Transl. Med. 15 694 2023 eade5855
212 Maher C.M. Thomas J.D. Haas D.A. Longen C.G. Oyer H.M. Tong J.Y. Kim F.J. Small-molecule Sigma1 modulator induces autophagic degradation of PD-L1Autophagic degradation of PD-L1 by a Sigma1 modulator Mol. Cancer Res. 16 2 2018 243 255 29117944
213 Jeong S.D. Jung B.K. Ahn H.M. Lee D. Ha J. Noh I. Immunogenic cell death inducing fluorinated mitochondria‐disrupting helical polypeptide synergizes with PD‐L1 immune checkpoint blockade Adv. Sci. 8 7 2021 2001308
214 Zhu J. Li Y. Tian Z. Hua X. Gu J. Li J. ATG7 overexpression is crucial for tumorigenic growth of bladder cancer in vitro and in vivo by targeting the ETS2/miRNA196b/FOXO1/p27 axis Mol. Ther. Nucleic Acids 7 2017 299 313 28624205
215 Deng J. Thennavan A. Dolgalev I. Chen T. Li J. Marzio A. ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1-mutant lung cancer Nature cancer 2 5 2021 503 514 34142094
216 Bestion E. Rachid M. Tijeras-Raballand A. Roth G. Decaens T. Ansaldi C. Targeting PPT1 with ezurpimtrostat sensitives liver tumor to immunotherapy by switching cold into hot microenvironments bioRxiv 2023 2023 01. 18.524541
217 Li X. Hu L. Jin Y. Ji H. MA16. 05 PI3K/Akt/mTOR signaling orchestrates the phenotypic transition and chemo-resistance of small cell lung cancer J. Thorac. Oncol. 16 10 2021 S938 S939
218 PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux O'Donnell J.S. Massi D. Teng M.W. Mandala M. Seminars in Cancer Biology 2018 Elsevier
219 Mao D. Zhang Z. Zhao X. Dong X. Autophagy-related genes prognosis signature as potential predictive markers for immunotherapy in hepatocellular carcinoma PeerJ 8 2020 e8383
220 Chen H. Hu Z. Sang M. Ni S. Lin Y. Wu C. Identification of an autophagy-related lncRNA prognostic signature and related tumor immunity research in lung adenocarcinoma Front. Genet. 12 2021 767694
221 Alissafi T. Banos A. Boon L. Sparwasser T. Ghigo A. Wing K. Tregs restrain dendritic cell autophagy to ameliorate autoimmunity J. Clin. Invest. 127 7 2017 2789 2804 28581446
222 Li Q. Rao R. Vazzana J. Goedegebuure P. Odunsi K. Gillanders W. Shrikant P.A. Regulating mammalian target of rapamycin to tune vaccination-induced CD8(+) T cell responses for tumor immunity J. Immunol. 188 7 2012 3080 3087 22379028
223 Li J. Cai W. Yu J. Zhou S. Li X. He Z. Autophagy inhibition recovers deficient ICD-based cancer immunotherapy Biomaterials 287 2022 121651
224 Sharma G. Ojha R. Noguera-Ortega E. Rebecca V.W. Attanasio J. Liu S. PPT1 inhibition enhances the antitumor activity of anti-PD-1 antibody in melanoma JCI Insight 5 17 2020
225 Cui Y. Shi J. Cui Y. Zhu Z. Zhu W. The relationship between autophagy and PD-L1 and their role in antitumor therapy Front. Immunol. 14 2023 1093558
226 Chen H. Hu Z. Sang M. Ni S. Lin Y. Wu C. Identification of an autophagy-related lncRNA prognostic signature and related tumor immunity research in lung adenocarcinoma Front. Genet. 12 2021 767694
227 Alissafi T. Banos A. Boon L. Sparwasser T. Ghigo A. Wing K. Tregs restrain dendritic cell autophagy to ameliorate autoimmunity The Journal of clinical investigation 127 7 2017 2789 2804 28581446
228 van Duijn A. Van der Burg S.H. Scheeren F.A. CD47/SIRPα axis: bridging innate and adaptive immunity J Immunother Cancer 10 7 2022
229 Nath P.R. Pal-Nath D. Kaur S. Gangaplara A. Meyer T.J. Cam M.C. Roberts D.D. Loss of CD47 alters CD8+ T cell activation in vitro and immunodynamics in mice OncoImmunology 11 1 2022 2111909
230 Dhupkar P. Gordon N. Stewart J. Kleinerman E.S. Anti-PD-1 therapy redirects macrophages from an M2 to an M1 phenotype inducing regression of OS lung metastases Cancer Med. 7 6 2018 2654 2664 29733528
231 Ou P. Wen L. Liu X. Huang J. Huang X. Su C. Thioesterase PPT1 balances viral resistance and efficient T cell crosspriming in dendritic cells J. Exp. Med. 216 9 2019 2091 2112 31262842
232 Chang L.C. Chen T.P. Kuo W.K. Hua C.C. The protein expression of PDL1 is highly correlated with those of eIF2α and ATF4 in lung cancer Dis. Markers 2018 2018 5068701
233 Qiao Y. Choi J.E. Tien J.C. Simko S.A. Rajendiran T. Vo J.N. Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer Nat Cancer 2 2021 978 993 34738088
234 Limagne E. Nuttin L. Thibaudin M. Jacquin E. Aucagne R. Bon M. MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells Cancer Cell 40 2 2022 136-52.e12
235 Lee E.J. Tournier C. The requirement of uncoordinated 51-like kinase 1 (ULK1) and ULK2 in the regulation of autophagy Autophagy 7 7 2011 689 695 21460635
236 Marei H.E. Hasan A. Pozzoli G. Cenciarelli C. Cancer immunotherapy with immune checkpoint inhibitors (ICIs): potential, mechanisms of resistance, and strategies for reinvigorating T cell responsiveness when resistance is acquired Cancer Cell Int. 23 1 2023 64 37038154
237 Pellegrini P. Strambi A. Zipoli C. Hägg-Olofsson M. Buoncervello M. Linder S. De Milito A. Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies Autophagy 10 4 2014 562 571 24492472
238 Zhang Y. Sha R. Zhang L. Zhang W. Jin P. Xu W. Harnessing copper-palladium alloy tetrapod nanoparticle-induced pro-survival autophagy for optimized photothermal therapy of drug-resistant cancer Nat. Commun. 9 1 2018 4236 30315154
239 Ebada H.M.K. Nasra M.M.A. Nassra R.A. Abdallah O.Y. Chondroitin sulfate-functionalized lipid nanoreservoirs: a novel cartilage-targeting approach for intra-articular delivery of cassic acid for osteoarthritis treatment Drug Deliv. 29 1 2022 652 663 35188017
240 Luo J. Zhang Z. Zeng Y. Dong Y. Ma L. Co-encapsulation of collagenase type I and silibinin in chondroitin sulfate coated multilayered nanoparticles for targeted treatment of liver fibrosis Carbohydr. Polym. 263 2021 117964
241 Cheng Y. Wang C. Wang H. Zhang Z. Yang X. Dong Y. Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy BMC Med. 20 1 2022 411 36303207
242 Zhu S. Zhang T. Zheng L. Liu H. Song W. Liu D. Combination strategies to maximize the benefits of cancer immunotherapy J. Hematol. Oncol. 14 1 2021 156 34579759
243 Liu T. Zhang J. Li K. Deng L. Wang H. Combination of an autophagy inducer and an autophagy inhibitor: a smarter strategy emerging in cancer therapy Front. Pharmacol. 11 2020 408 32322202
244 Tonkin-Reeves A. Giuliani C.M. Price J.T. Inhibition of autophagy; an opportunity for the treatment of cancer resistance Front. Cell Dev. Biol. 11 2023 1177440
245 Infante J.R. Somer B.G. Park J.O. Li C.-P. Scheulen M.E. Kasubhai S.M. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas Eur. J. Cancer 50 12 2014 2072 2081 24915778
246 Kinsey C.G. Camolotto S.A. Boespflug A.M. Guillen K.P. Foth M. Truong A. Protective autophagy elicited by RAF→ MEK→ ERK inhibition suggests a treatment strategy for RAS-driven cancers Nat. Med. 25 4 2019 620 627 30833748
247 Smith B.D. Vogeti L. Gupta A. Singh J. Al-Ani G. Bulfer S.L. Preclinical studies with DCC-3116, an ULK kinase inhibitor designed to inhibit autophagy as a potential strategy to address mutant RAS cancers Mol. Cancer Therapeut. 18 2019
248 Moretti F. Bergman P. Dodgson S. Marcellin D. Claerr I. Goodwin J.M. TMEM 41B is a novel regulator of autophagy and lipid mobilization EMBO Rep. 19 9 2018 e45889
249 Morita K. Hama Y. Izume T. Tamura N. Ueno T. Yamashita Y. Genome-wide CRISPR screen identifies TMEM41B as a gene required for autophagosome formation JCB (J. Cell Biol.) 217 11 2018 3817 3828 30093494
250 van Vliet A.R. Chiduza G.N. Maslen S.L. Pye V.E. Joshi D. De Tito S. ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation Mol. Cell 82 22 2022 4324 4339. e8 36347259
251 Chou H.-Y. Lee Y.-T. Lin Y.J. Wen J.-K. Peng W.-H. Hsieh P.-L. PTPN9-mediated dephosphorylation of VTI1B promotes ATG16L1 precursor fusion and autophagosome formation Autophagy 17 10 2021 2750 2765 33112705
252 Kumar S. Gu Y. Abudu Y.P. Bruun J.-A. Jain A. Farzam F. Phosphorylation of syntaxin 17 by TBK1 controls autophagy initiation Dev. Cell 49 1 2019 130 144. e6 30827897
253 Kocak M. Ezazi Erdi S. Jorba G. Maestro I. Farrés J. Kirkin V. Targeting autophagy in disease: established and new strategies Autophagy 18 3 2022 473 495 34241570
254 Békés M. Langley D.R. Crews C.M. PROTAC targeted protein degraders: the past is prologue Nat. Rev. Drug Discov. 21 3 2022 181 200 35042991
