
==== Front
Transl Oncol
Transl Oncol
Translational Oncology
1936-5233
Neoplasia Press

S1936-5233(24)00213-4
10.1016/j.tranon.2024.102086
102086
Review Article
Photoimmunotherapy for cancer treatment based on organic small molecules: Recent strategies and future directions
Zhao Deming
Wen Xin
Wu Jiani
Chen Feihong chenfeihong@seu.edu.cn
⁎
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
⁎ Corresponding author. chenfeihong@seu.edu.cn
24 8 2024
11 2024
24 8 2024
49 1020863 6 2024
25 7 2024
11 8 2024
© 2024 Published by Elsevier Inc.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Highlights

• The revelation that photodynamic therapy may induce immunogenic cell death, consequently triggering abscopal effect akin to radiotherapy, has emerged.

• Structural optimization of the photosensitizer not only increases reactive oxygen species production but also enhances organelle targeting and intracellular metabolic capacity, resulting in a more efficient induction of immunogenic cell death.

• The introduction of additional components, such as immune checkpoint inhibitors, delivered concurrently, allows for the formulation of personalized strategies tailored to specific scenarios.

• The integration of multiple components introduces challenges, including potential conflicts in therapeutic effects, issues of toxicity and metabolism, and the crucial need for carefully selecting in vivo models to assess photoimmunotherapy. Addressing these challenges is imperative for the swift clinical translation of this promising approach.

Photodynamic therapy (PDT) is considered as a promising anticancer approach, owning to its high efficiency and spatiotemporal selectivity. Ample evidence indicated that PDT can trigger immunogenic cell death by releasing antigens that activate immune cells to promote anti-tumor immunity. Nevertheless, the inherent nature of tumors and their complex heterogeneity often limits the efficiency of PDT, which can be overcome with a novel strategy of photo-immunotherapy (PIT) strategy. By exploring the principles of PDT induction and ICD enhancement, combined with other therapies such as chemotherapy or immune checkpoint blockade, the tailored solutions can be designed to address specific challenges of drug resistance, hypoxic conditions, and tumor immunosuppressive microenvironments (TIMEs), which enables targeted enhancement of systemic immunity to address most distant and recurrent cancers. The present article summarizes the specific strategies of PIT and discusses recent existing limitations. More importantly, we anticipate that the perspectives presented herein will help address the clinical translation challenges associated with PIT.

Graphical abstract

Image, graphical abstract

Keywords

Photodynamic therapy
Immunogenic cell death
Immunotherapy
Photo-immunotherapy
Abbreviations

AIE Aggregation-induced emission

ALA Aminolevulinic acid

ANXA1 Annexin A1

APCs Antibody-photosensitizer conjugates

ATP Adenosine triphosphate

BODIPY Boron dipyrromethene

CDT Chemo dynamic Therapy

Ce6 Chlorin e6

CTLA-4 Cytotoxic T-lymphocyte-associated protein 4

CTLs Cytotoxic T lymphocyte

Cys Cysteine

DAMPs Damage associated molecular patterns

DCs Dendritic cells

EGFR Epidermal Growth Factor Receptor

EMT Epithelial-mesenchymal transition

EPR Enhanced permeability and retention

GBM Glioblastoma

Gef Gefitinib

GSH Glutathione

HCC Hepatocellular carcinoma

HDACs Histone deacetylases

HMGB1 High mobility group box 1 protein

HpD Hematoporphyrin derivative

irAE Immune-related adverse event

ICB Immune checkpoint blockade

ICD Immunogenic cell death

IDO Indoleamine2,3-dioxygenase

IFNs I interferon

Ir Iridium

ISC Intersystem crossing

KRAS Kirsten rat sarcoma

LA Lactic acid

MDSCs Myeloid-derived suppressor cells

NF-κB Nuclear factor-κB

NIR Near-infrared region

NK Natural killer (cell)

NP Nanoparticle

NSCLC Non-small cell lung cancer

ODN Oligodeoxynucleotide

Ola Olaparib

pDC Plasmacytoid dendritic cells

PDT Photodynamic therapy

PD-1/PD-L1 Programmed cell death protein 1/Ligand 1

PEG Polyethylene glycol

PGA Polyglutamic acid

PIT Photo-immunotherapy

PLGA Poly lactic-co-glycolic acid

PS Photosensitizer

PTX Paclitaxel

ROS Reactive oxygen species

Ru Ruthenium

SOC Spin-orbit coupling

Sal-B Salvianic acid B

TAMs Tumor-associated macrophages

TARF Tetraacetylriboflavin

TGF-β Transforming growth factor

TIME Tumor immunosuppressive microenvironment

TKI Tyrosine kinase inhibitors

TLR9 Toll-like receptor 9

Tregs Regulatory cells
==== Body
pmcIntroduction

The pathophysiological process of cancer involves multiple factors [1]. Traditional methods such as surgery, radiation therapy and chemotherapy have limitations in their influence on normal tissues and addressing recurrence and metastasis [2]. Current cancer research encompasses various fields, such as tumor vaccines, gene editing and precision medicine [3,4]. The intricate nature of cancer emphasizes the necessity for more effective treatment and detection methods.

Immunotherapy is a potentially promising primary anti-cancer treatment strategy [5]. It encompasses immune checkpoint inhibitors such as indoleamine 2,3-dioxygenase (IDO), programmed cell death protein 1/Ligand 1 (PD-1/PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, monoclonal antibody therapy represented by Erbitux and CAR-T therapy, which have been demonstrated to enhance tumor antigen recognition and block immune receptors, reverse the tumor immunosuppressive microenvironment (TIME), and subsequently eliminate tumors [[6], [7], [8], [9], [10]]. However, a considerable proportion of patients exhibit low response rates to immunotherapy, thereby facilitating the approach of combining immunotherapy with other treatments, demonstrating their favorable prospects [[11], [12], [13]]. As an emerging treatment modality that utilizes specific wavelengths to stimulate photosensitizer (PS), photodynamic therapy (PDT) could result in the production of reactive oxygen species (ROS) to induce cytotoxicity in tumor cells [14]. Findings showed that during the process of PDT, immunogenic cell death (ICD) occurs, leading to the release of a series of damage associated molecular patterns (DAMPs) including high mobility group protein B1 (HMGB1), adenosine triphosphate (ATP) and heat-shock proteins (HSPs), which ultimately activates innate and adaptive immune responses, leading to immunotherapeutic effects [[15], [16], [17]].

The concept of photoimmunotherapy (PIT) combines immunotherapy with PDT. The similar “NIR-PIT” concept was first proposed by Hisataka Kobayashi [18,19]. Inspired by the phenomenon of ICD, the concept of PIT has been expanded. This review aims to categorize the latest strategies for achieving PIT and elucidate their mechanisms of action. The clinical translation of PIT still faces many challenges, it is hoped that this paper will provide a clearer exposition for peer research.

Immune-based cancer therapy

In recent decades, significant progress has been made in cancer immunotherapy. Compared to traditional treatments, immunotherapy harnesses the host's own immune system, thereby possessing innate superior specificity. A complete and effective immune response cycle typically involves several basic steps: (1) Cancer cell death releases antigens. (2) Antigen-presenting cells (APCs), such as dendritic cells, contain present antigens. (3) Antigen-presenting cells and T cells are activated. (4) T cells migrate to the tumor sites. (5) T cells infiltrate the tumor and stroma. (6) T cells recognize cancer cells (while activated T cells aggregate in the stroma, B cells interact with immune cells to maintain their effector state and function). (7) Immune cells kill cancer cells, and dead cells release antigens for the next cycle [20]. A more detailed cancer immune cycle with activating and inhibitory factors is shown in Fig. 1.Fig. 1 Detailed immune response and influencing factors. APCs: Antigen Presenting Cells; ATP: Adenosine Triphosphate; b2M: Beta-2 Micro globulin; CCL2/5/19/21: Chemokine (C—C motif) Ligand 2/5/19/21; CD155-TIGIT: CD155-T cell Immunoreceptor with Ig and ITIM domains; CD28-B7.1: CD28-B7.1 Co-stimulatory Molecules; CD40-CD40L: CD40-CD40 Ligand Co-stimulatory Molecules; CTLA-4-CD28: Cytotoxic T-lymphocyte-associated protein 4-CD28; CXCL3/9/10/11/12: Chemokine (C-X-C motif) Ligand 3/9/10/11/12; ERVs: Endogenous Retroviruses; HLA-G: Human Leukocyte Antigen-G; IFN-α/γ: Interferon-alpha; IL-2/6/10/12: Interleukin-2/6/10/12; LAG-3: Lymphocyte-activation gene 3; LAIR-1: Leukocyte-associated immunoglobulin-like receptor 1; LFA-1-ICAM1: Lymphocyte function-associated antigen 1-Intercellular adhesion molecule 1; l-selectin: Lymphocyte Selectin; MDSCs: Myeloid-derived suppressor cells; MMP-2/9: Matrix Metalloproteinase-2/9; NETs: Neutrophil Extracellular Traps; STING: Stimulator of Interferon Genes; Siglecs-Sialic Acids: Sialic-acid-binding immunoglobulin-type lectins; TAAs: Tumor-associated Antigens; TCR-pMHC: T-cell Receptor-peptide-Major Histocompatibility Complex; TGF-β: Transforming Growth Factor-beta; TME Gradients: Tumor Microenvironment Gradients; TNF-α: Tumor Necrosis Factor-alpha; TREM2: Triggering receptor expressed on myeloid cells 2; Treg cells: Regulatory T cells; VCAM-1: Vascular Cell Adhesion Molecule 1; VEGF: Vascular Endothelial Growth Factor; VLA-1/2/4: Very Late Antigen-1/2/4; VSIG4: V-set and Immunoglobulin domain containing 4.

Fig. 1

Based on the above figure, strategies for cancer immunotherapy have been developed and are listed in Table 1. These strategies mainly target one or more of the steps mentioned above or specific immune cells. Depending on their mode of action, they can be primarily classified into two types [21]. One type directly enhances immune responses, such as cancer vaccine therapy, whereas the other involves indirect approaches, reversing the immunosuppressive microenvironment, such as Tregs and myeloid-derived suppressor cells (MDSCs), restoring dysregulated metabolism, and blocking immune checkpoint pathways such as PD-1/PD-L1 and CTLA-4.Table 1 Classic immunotherapy strategies.

Table 1Cancer treatment strategy	Principle and method	Steps/immune cells targeted	Ref.	
ICB	Immune checkpoints such as PD-1/PD-L1 and CTLA-4 are crucial molecules in negative regulation of immune activation. ICB exerts its effect by blocking the inhibitory receptors on cytotoxic T lymphocytes (CTLs).	T cells, particularly CTLs	[22]	
Adoptive cell therapy	Adoptive cell therapy involves isolating autologous immune cells, expanding them in vitro, and reintroducing them into patients to enhance their anticancer capabilities. It is more suitable for non-solid tumors and can be broadly classified into two categories based on specificity.	Tumor-infiltrating lymphocytes (TILs) Engineered T cell receptors (TCRs) Chimeric antigen receptor (CAR) T cells Natural killer (NK) cells	[23]	
Tumor-specific vaccines	Tumor-specific vaccines are a form of active immunotherapy targeting tumor antigens. By introducing specific antigens, they enhance immunogenicity and activate the patient's own immune system. They can be based on cells, DNA, mRNA, peptides, dendritic cells, etc.	Antigen release and presentation	[3]	
Non-specific immune modulation	Non-specific immune modulation involves the use of immunomodulators to enhance the body's immune function in a non-specific manner. Examples include Bacille Calmette-Guérin (BCG), mushroom polysaccharides, and cytokines such as IL-2.	Macrophages, natural killer cells, and cytotoxic T lymphocytes	[24]	
Gene therapy	Gene therapy involves identifying underlying pathological mechanisms through genome screening. It can also involve introducing exogenous target genes via vectors to correct the activation of oncogenes or activate tumor suppressor genes, such as oncolytic virus therapy.	Targeted gene modifications	[25]	
Downregulation of immunosuppressive cells	Targeting dysregulated immunosuppressive cell levels in the immune microenvironment. For example, CXCR1/2 inhibitor SX-682 can inhibit MDSC trafficking, [26]and histone demethylase inhibitors can inhibit Tregs [27].	M2-type macrophages, MDSCs, and Tregs	[28]	
Small molecule immunotherapeutics	Immunomodulatory small molecule inhibitors target intracellular pathways such as pattern recognition receptors, oncogenic signals, and metabolic pathways and can serve as complementary or alternative therapies. For example, pexidartinib is a small molecule targeting the KIT pathway with immunomodulatory properties [29].	PPR-related pathways, immune checkpoints, cytokines and chemokines, retinoic acid receptor-related orphan receptor gt, metabolic pathways, oncogenic pathways, and immune kinases	[30,31]	

Unfortunately, many of these methods are applicable only to a small subset of cancers or to specific cases. The body's own immune system is in a delicate balance, and most treatment strategies involve carry immune-related adverse events (irAEs), such as thyroid dysfunction and autoimmune diabetes. [32] Moreover, clinical response rates remain low. In most cases, only 20–40 % of patients respond to PD-1/PD-L1 antibodies, with even fewer achieving long-term remission. Approximately 15 % of patients respond to the monoclonal antibody ipilimumab targeting CTLA-4, and clinical trials of IDO1 inhibitors have failed [33]. Typically, the low responsiveness to immunotherapy can be attributed to the tumor's immunosuppressive nature, often characterized as a “cold tumor”. In such cases, there is often a breakdown in antigen presentation or T cell infiltration, accompanied by the presence of an immunosuppressive tumor microenvironment. Therefore, converting “cold” tumors into “hot” ones is a step toward developing synergistic immunotherapies. Fortunately, there is hope placed in the discovery of ICD.

The concept of ICD was formally proposed in 2005 to describe cell death capable of inducing an immune response, leading to adaptive immunity against antigens released by dying cells. Immunogenic cell death can be induced by various stressors, such as bacterial or viral infections, chemotherapy drugs, radiotherapy, and PDT. Ferroptosis, necroptosis, pyroptosis, and autophagy are various forms of ICD. Although, these forms exhibit different characteristics, they share the common feature of releasing tumor-associated antigens (TAAs) and DAMPs. Furthermore, DAMPs released during ICD include calcium-binding proteins and heat shock proteins (HSPs) exposed on the cell surface, high mobility group box 1 (HMGB1), annexin A1 (ANXA1), adenosine triphosphate (ATP), and type I interferons (IFNs). These DAMPs enhance the recruitment and maturation of antigen-presenting cells (APCs), thereby promoting the maturation and differentiation of T cells into cytotoxic T lymphocytes (CTLs) [34]. ATP emits a “find me” signal that attracts APCs and activates T cells. Moreover, HSPs such as HSP70 and HSP90 translocate to the cell membrane surface, emitting an “eat me” signal that can be recognized by NK cells for direct killing. Additionally, HMGB1, protein, as a proinflammatory factor, also interacts with dendritic cell (DC) receptors and stimulates tumor antigen presentation. Finally, the released ANXA1 aids in the migration of dendritic cells (DCs) to dying cancer cells [35]. Moreover, released interferons, tumor necrosis factor, and interleukins also contribute to the immune response. However, effectively triggering controlled ICDs in a controlled manner poses new challenges.

Cancer treatment based on photodynamic therapy and its role in immunotherapy

Principles of PDT

The three main components of PDT are PS, laser and oxygen. When the PS accumulates at tumor site, laser irradiation could cause the PS to transition from a stable low-energy state to an excited singlet state. This state is unstable and releases energy in the form of heat or fluorescence. In this state, the electron of the molecule undergoes spin inversion to enter the excited triplet state, where it can release energy through fluorescence or return to the ground state through two pathways. The Type I pathway involves the generation of cytotoxic substances such as superoxide anion radicals (O2-), hydroxyl radicals (OH-) and hydrogen peroxide (H2O2) through electron transfer with the substrate, while the Type II pathway produces singlet oxygen (1O2) through energy transfer, thereby promoting cell necrosis and apoptosis (Fig. 2) [36]. The Type II mechanism is currently a widely studied aspect of PDT. PDT possesses high spatial and temporal selectivity as well as specific targeting characteristics, and does not result in obvious drug resistance. Consequently, it has become a highly promising therapy to be widely studied. Additionally, since PDT was found to induce a “Abscopal effect” similar to radiotherapy, increasing evidence suggests that PDT can also induce ICD.Fig. 2 The mechanism of action of PDT.

Fig. 2

Development and classification of photosensitizers

The development of PSs has been divided into three generations. First-generation PSs, such as porfimer sodium, are derived from purified hematoporphyrin derivatives (HpDs) and are excited by light at a wavelength of 630 nm to generate ROS, causing damage to tumor cells and vessels. Second-generation PSs, such as 5-aminolevulinic acid (ALA), have an excitation wavelength of 635 nm, which allows for deeper penetration and a broader therapeutic range. Third-generation PSs are currently linked with biological molecules, such as antibodies or peptides, to achieve tumor specificity. Based on the elemental categories of the active agents, PSs can be classified into transition metal coordination complexes, organic fluorophores (metal-organic hybrids), and semiconductor polymer nanoparticles. Representative PSs approved or tested in a clinical setting are listed in Table 2.Table 2 Representative photosensitizers entering or approved for clinical use.

Table 2Type	Chemical name	Current status	Cancer types	Ref.	
Organic fluorophores	Porfimer sodium	Approved in over 40 countries	Lung cancer, esophageal cancer, and recurrent superficial papillary bladder cancer	[37]	
5-aminolevulinic acid	Australia approved for marketing	Skin cancer, bladder cancer, gastrointestinal cancer, and lung cancer	[38]	
Talaporfin	Japan approved for marketing	Esophageal cancer, brain cancer, and lung cancer	[39]	
Cardio-Green	USA, Japan, and Nordic countries approved for marketing	Cervical cancer, breast cancer, melanoma, and neurogenic tumors	[40]	
Temoporfin	Phase II clinical trial	Mesothelioma, diffuse malignant mesothelioma, oral tumors, and colorectal cancer	[41]	
Chlorin e6	Phase II clinical trial	Non-small cell lung cancer	[42]	
Transition metal complex	Padeliporfin	EU approved for marketing	Prostate adenocarcinoma, renal pelvis and ureteral epithelial carcinoma	[43]	
Sulfonated aluminum phthalocyanine	Russia approved for marketing	Lung cancer, liver cancer, and gastrointestinal cancer	[44]	
Zinc phthalocyanine	Phase I clinical trial	Oral cancer, skin cancer, and esophageal cancer	[45]	
TLD-1433	Phase II clinical trial	Carcinoma in situ, non-muscle-invasive bladder tumor, and bladder cancer	[46]	
Motexafin lutetium	Phase II clinical trial	Breast cancer, cervical carcinoma in situ, and cervical intraepithelial neoplasia	[47]	

Most of the clinically approved PSs in the above table are small organic molecules and some transition metal complexes because they possess unique pharmacokinetic characteristics and photophysical properties. However, the short excitation wavelengths of most PS (400–700 nm) and the hypoxic nature of tumor sites pose considerable challenges for PS development. Furthermore, an ideal PS should exhibit the following features: light absorption in the near-infrared (NIR) region, efficient ROS generation, low dark toxicity and easy metabolism. The heavy atom effect mediated strong spin-orbit coupling (SOC) and efficient intersystem crossing (ISC) of ruthenium (Ru) and iridium (Ir) elements ensure a large stokes shift, making metal-based PSs highly preferred. Additionally, Ru and Ir have diverse coordination preferences in laboratory research, and their complexes often show potent catalytic activity and selectivity, effectively participating in organic synthesis processes, including hydrogen bond activation and asymmetric synthesis, thereby providing greater potential for PS development. The present review summarizes small organic PSs including metal-based complexes containing Ru, Ir, and organic fluorophores.

Delivery of photosensitizers

Targeted strategies can improve the delivery of PSs to tumor tissues, potentially enhancing the selectivity and efficacy of PDT, which has attracted widespread attention. Passive and active targeting methods are currently being investigated for this purpose. Passive targeting can be achieved by adjusting the size and surface chemistry of nanoparticle (or macromolecular) formulations to promote their selective accumulation in tumors via enhanced permeability and retention (EPR) effect. Active targeting typically involves the use of highly targeted ligands that bind to specific surface molecules expressed primarily by cancer cells or tumor epithelial cells. Various ligands have been explored for active targeting of PDT drugs, including peptides, proteins and nucleic acid aptamers (Fig. 3). Alternatively, nanotechnology has been employed to enhance drug delivery by addressing oxygen deficiency using manganese dioxide, enhancing light penetration depth through gold nano-cages, utilizing upconversion luminescent materials for improved optical properties, and employing polyethylene glycol (PEG) with excellent biocompatibility.Fig. 3 Active targeting delivery strategies for photosensitizers.

Fig. 3

Induction and enhancement of immune response by photodynamic therapy

Abnormal cell proliferation and vascular distortion at tumor sites, coupled with hypoxia and high levels of glutathione, often lead to residual tumor cells escaping under traditional PDT, rendering it ineffective against recurrence and metastasis. However, PDT can serve as an inducer of ICD or macrophage polarization processes to stimulate the immune system, thereby counteracting the “cool” immunosuppressive tumor environment and turning it “hot”. The combination of PDT and immunotherapy is naturally considered a viable new concept for overcoming the shortcomings of individual immunotherapies in cancer treatment. The “NIR-PIT” was first proposed by Hisataka Kobayashi, and it involves the use of monoclonal antibodies conjugated with the PS IR700, targeting specific membrane molecules using near-infrared light.

At present, the primary strategies of PIT can be divided into two categories. The first category involves targeting processes and elements in the immune cycle, synergizing with PS to play a multifunctional role. The second category focuses on the PS itself inducing a more potent ICD effect. Several typical examples include RM-1929 (a cetuximab conjugate drug using IRDye700DX as the PS), protoporphyrin, and redaporfin, which hold orphan drug status as ICD inducers in cancer treatment [48]. Thus, this paper provides a summary of small molecule organic PSs including Ru and Ir metal-based complexes.

Synergistic immunotherapeutic strategies based on photodynamic therapy

Chemotherapy

Certain cancer chemotherapeutical drugs, like anthracyclines, camptothecin derivatives (e.g., paclitaxel, doxorubicin, oxaliplatin), induce ICD and have immunomodulatory capabilities [49]. Combining PDT with chemotherapy is a potential strategy to boost ICD and activate systemic immunity.

Fang et al. connected chlorin e6 (Ce6) with polyglutamic acid (PGA) and encapsulated olaparib (Ola) to form PCO nanoparticles (NPs). They then extracted the cell membrane of mouse 4T1 cells to coat the NPs, resulting in MPCO (Fig. 4a) [50]. The glutathione (GSH) in the tumor microenvironment (TME) cleaves the cysteine (Cys) disulfide bond and releases PDT to damage the nuclear DNA. Ola, as a PARP inhibitor, hinders DNA damage repair, and the enhanced DAMPs promote the maturation of DCs and infiltration of killer T lymphocytes, especially by activating long-term immunity in vivo.Fig. 4 Schematic illustration of PDT in combination with chemotherapy, ICB and immunologic adjuvant.

Fig. 4

Kang et al. designed a d-A-D type compound with low-bandgap chromophores and encapsulated it with poloxamer. They also converted the chemotherapeutic drug paclitaxel (PTX) into a hypoxia-releasing prodrug, and both were co-delivered by the membrane of M1-type macrophages [51]. PDT generates ROS, intensifying the oxygen-consuming triggering release of PTX. The synergistic effect of PDT and chemotherapy induces ICD, thereby inhibiting both primary and distant tumors. Olga et al. designed a riboplatin Pt(IV) prodrug with tetraacetylriboflavin (TARF) in the axial position of vitamin B2 [52]. This is the first observation of the blue light-activated release of cisplatin and ROS, demonstrating a dual action of PDT/photoactivated chemotherapy (PACT).

Immune-checkpoint blockade

Despite the notable success of immune checkpoint therapy (ICT) in cancer treatment [53], challenges like ineffectiveness, irAE, and resistance persist [54,55]. To address suboptimal response rates, combination therapies involving ICT are deemed essential [56,57]. PDT, known for inducing ICD, often lacks robust distant effects. Ongoing research focuses on optimizing immunogenicity through synergistic approaches with ICT [58,59].

PD-1/PD-L1 has gained clinical approval for treating various cancers [60,61]. Lou et al. investigated the immune mechanisms of repeated PDT and repeated PDT + α-PD-1 in a highly invasive murine tumor model. They observed the activation of innate immunity, a greater tendency for antigen presentation in the spleen, and draining lymph nodes of distant tumors. Simultaneously, the proportion of CD4+ T-cell subgroups in the spleen changed and the proportion of CD8+ T cells increased in the draining lymph nodes of non-irradiated distant tumors. R-PDT + αPD-1 exhibited mild laboratory tumor dissolution, and there was no apparent inflammation in the vital organs of both mouse models [62].

IDO, overexpressed in tumors, catalyzes the metabolism of tryptophan into kynurenine, inhibiting the growth of effector T cells and cytotoxic T cells, ultimately leading to immune escape [63]. Zheng et al. targeted the cascade immune activation process and constructed a self-delivering collaborative therapeutic drug, CeNB (Fig. 4b). Ce6, BMS-1, and NLG919 were self-assembled for this purpose. PDT led to the regression of primary tumors, inducing ICD effects. The study inhibited IDO expression, promoted the activation of effector T cells, and the blockade of PD-1/PD-L1 avoided immune escape, achieving long-term immunity and resistance to tumor metastasis [64]. This study provides a multifaceted synergistic strategy.

Immunologic adjuvant

The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) through pattern-recognition receptors, leading to the activation of innate immune cells and subsequent adaptive immune responses. Since the discovery of this phenomenon, immunologic adjuvants have been commonly used to stimulate the immune system for more effective recognition of tumor antigens [65,66]. Adjuvants can be classified into two types based on immunogenicity. Strengthening the immune response elicited by PDT involves the deployment of synergistic immunological adjuvants, representing a feasible scheme.

Toll-like receptor 9 (TLR9) initializes the cellular immune responses. CpG oligodeoxynucleotide (CpG ODN) activates plasmacytoid dendritic cells (pDC) and TLR9-expressing B cells. [[67], [68], [69]] Meng et al. aimed to reduce postoperative tumor recurrence by constructing a nanostructure M@PFC, incorporating the immunologic adjuvant CpG and a photosensitivity agent (PF3-PPh3) (Fig. 4c) [70]. Both were electrostatically adsorbed onto a poly lactic-co-glycolic acid (PLGA) matrix and subsequently enveloped by a macrophage membrane. At a concentration of 25 μg/mL, there was no apparent dark toxicity, and 4T1 cells, after uptake for 24 h, exhibited a significant increase in ROS production upon 5 min of white light exposure. The hemolysis rate of @PFC < 5 % (water considered as 100 %). An incomplete excision model of in situ 4T1 tumor recurrence was established, revealing that the inhibitory effect on tumor growth rate was greater in the M@PFC + Light group than in the individual CpG ODN and M@PF + Light groups. Additionally, the proportion of CD4+ T cells and CD8+ T cells significantly increased in the peripheral blood of the restructured mice, and the elevation of TNF-α in tumor tissue was most pronounced. The findings of this study demonstrates a promising approach for co-delivering immunological adjuvants to inhibit tumor recurrence.

M1 type macrophages are involved in active immune response, whereas M2 macrophages are involved in immunosuppression. It is known that TLR7/8 agonists polarize M2-type to M1-type tumor-associated macrophages (TAMs) through the nuclear factor-κB (NF-κB) signaling pathway. Conventional TLR7/TLR8 agonists have serious side effects attributable to their unfavorable pharmacokinetics and specificity, and the emergence of targeted peptides can address this urgent issue. Liu et al. prepared a chimeric peptide-engineered self-delivering nanodrug, ChiP-CeR [71]. Ce6 and the TLR7/8 agonist imiquimod (R837), self-assembled into NPs (CeR) through non-covalent interactions, and were then modified with a tumor matrix targeting peptide (ChiP) to target the high expression of fibronectin at the tumor site. The analysis confirmed an approximately a 2.5-fold increase in CRT expression and a 46 % reduction in HMGB1 expression. Co-incubation of IL-4 with macrophages in vitro resulted in a 1.5-fold increase in the proportion of M1 macrophages (F4/80+ CD80+ cells) in the ChiP-CeR group. In an in vivo model, Tregs cells were significantly decreased, and the growth of metastatic tumors was inhibited.

An optimal immune response entails a cascade of intricate processes, spanning antigen presentation, processing, recognition, and subsequent cytotoxicity. The diverse factors contributing to reduced immune response rates in certain cases underscore the investigation of specific immunologic adjuvants as promising complements for customizing PDT interventions.

Reprogramming of the tumor microenvironment

The tumor microenvironment (TME) refers to the internal environment that includes tumor cells, stromal cells and endothelial cells. Metabolites, growth factors and cytokines in the environment influence the growth and behavior of tumor cells. Reprogramming of the TME typically involves metabolic regulation and interactions between tumor cells and surrounding cells to adapt to the growth and metastatic needs of the tumor [72]. One significant hallmark of cancer is metabolic reprogramming, allowing cells to acquire energy in the TME to sustain proliferation and progression, including mitochondrial oxidative phosphorylation, glutamine metabolism, and aerobic glycolysis [73]. Capturing and intervening in these pathways during PDT are crucial strategies to overcome cancer.

Zhao et al. have developed a photodynamic immune-stimulator, BVC, comprising three components. After self-assembly, it exhibited excellent stability, facilitating intra-tumoral drug delivery and uptake. Ce6 targets primary tumor regression and induces ICD. V9302, through glutamine metabolism reprogramming, ultimately inhibited glutathione (GSH) synthesis, upregulated Fas and PD-L1, activated immune responses, induced DC maturation, and promoted CD8+ T-cell recognition; BMS-1 blocked PD-1/PD-L1 expression and enhanced T-cell recognition. This synergistic effect enhances immune recognition and blocks immune escape (Fig. 5a) [74].Fig. 5 Example diagram of PDT in collaboration with TME reprogramming.

Fig. 5

Glioblastoma (GBM) is highly invasive, and even ICB therapy has limited efficacy, owning to the TIME and the blood-brain barrier. Intracellular and extracellular cholesterol levels are closely associated with PD-1/PD-L1 expression, invasive pseudopods, and endoplasmic reticulum stress. The blood-brain barrier prevents cholesterol passage in GBM, isolating cholesterol metabolism and making it a potential target [[75], [76], [77]]. Liu et al. designed a nanovesicle that penetrates tumors, delivers PS and avasimibe, and assists in enhancing PDT by blocking cholesterol metabolism. The iRGD peptide used in the particle enhanced tumor-targeting penetration [78].

Hypoxia during PDT is an inherent challenge, primarily because of active anaerobic glycolysis in cancer cells, known as the “Warburg” effect. Targeting glucose metabolism is an efficacious strategy [74,79]. Su et al. utilized S-S-OSCLMs to co-load Ce6, salvianolic acid B (Sal-B), and Fe3+ coordinated with Sal-B to obtain the nano-drug C&S/Fe@S-S-OSCLMs. In vivo, this formulation suppressed glucose uptake and glycolysis, reshaping the hypoxic TME and substantially improving the therapeutic efficacy of PDT in tumor-bearing mice (Fig. 5b) [80]. The main components have optimal clinical applicability and safety [81,82].

Jia et al. designed a bio-degradable pseudo-conjugate polymer acting as a PS and self-assembled it with an oxidation-sensitive diselenide-containing polymer and the vascular growth-related kinase inhibitor regorafenib, resulting in NP-PDT@Reg (Fig. 5c) [83]. Observations in the K7M2 hetero-transplantation model revealed higher apoptotic rates and singlet oxygen production. Regorafenib promotes macrophage phenotype conversion from M2 and M1, alleviates vascular normalization and hypoxic conditions. The optimized PDT effect induced ICD and dendritic cell maturation, presenting an innovative approach for enhancing photodynamic effects by targeting the TME.

The TME also poses resistance mechanisms to conventional immunotherapies, such as the transforming growth factor (TGF-β)-mediated epithelial-mesenchymal transition (EMT) process and lactic acid (LA)-induced M2-type macrophages. Zhao et al. developed a nano-drug system with three components to reverse the TIME caused by TGF-β and LA (Fig. 5d) [84]. Ce6, as the PS component, SB505124 inhibited the type I receptor of TGF-β, and ionidamine inhibited LA. The resulting TerBio, administered intravenously, passively accumulated at the tumor site. Apart from the PDT effect, it blocked TGF-β and LA to reprogram the TME, enhancing immune therapy and inhibiting the growth of distant and metastatic tumors.

Beyond the aspects mentioned in this section, there are other “Reprogramming” processes that alter cell fate, such as protein reprogramming and extracellular environment reprogramming mentioned in other parts of this paper, as well as unexplored gene reprogramming. These concepts design different steps and aspects in the process of tumor development, representing a highly potential supplementary therapeutic approach.

Reprogramming of cell death

Activation of the immune system by PDT largely relies on the achievement of ICD. The currently known ICD pathways include pyroptosis, necroptosis, ferroptosis, and paraptosis, as well as unknown pathways. Combining PDT with cell death reprogramming to enhance ICD is a promising strategy [85].

Pyroptosis, as an ICD, has been demonstrated to be induced by PDT. By promoting innate immunity, PDT can reverse the TIME [86,87]. Building on this, Li et al. reported a nano platform containing the PS TBE and desatinib (Fig. 6a) [88]. Desatinib restored intracellular STING and GSDME levels. Additionally, PDT activates caspase-3 to generate the pyroptosis inducer GSDME-N terminal, leading to mitochondrial damage and the release of dsDNA, activating the STING signaling pathway. This synergistic mechanism enables the immune system to acquire tumor resistance to tumors and long-term memory.Fig. 6 Example diagram of PDT in collaboration with death reprogramming.

Fig. 6

Ferroptosis is primarily affected by iron (Fe) homeostasis and lipid peroxidation. In the early stages, DAMPs are released, which enhances the immune response. In recent years, PDT has been found to induce ferroptosis [89,90]. Naturally, the co-administration of ferroptosis inducers is also a tactic to reinforce ICD. Yang et al. designed a nano-delivery system carrying Ce6 and iFSP1 (inhibitor of ferroptosis suppressor protein 1) (Fig. 6b) [91]. In vitro experiments showed excellent performance compared with the performance obtained with Ce6 alone. In vivo models revealed that this approach synergistically augmented ferroptosis-induced ICD, subsequently activating the immune system and amplifying α-PD-L1 therapy. Another noteworthy investigation is the design by Fang et al. of the d-A structured organic PS PPR-2CN, which acts as a single component for triple impacts, including NIR-guided ferroptosis, type I PDT, and fluorescence imaging (Fig. 6c) [92]. Experimental analysis also revealed a small ∆ES1-T1 and a large SOC, enhancing ISC and promoting type I PDT.

The concept of necroptosis was proposed in 2005 [93]. Necroptosis induced by PDT was discovered in 2011 and has been relatively less studied [94]. To demonstrate the immunogenicity of necroptosis induced by PDT, Zhang et al. discovered a silicon phthalocyanine-based PS that induced cell death and formed the RIPK1-RIPK3-MLKL complex. They also ascertained the release of ATP and HMGB1 after PDT [95]. Additionally, Niu et al. devised a PS TBMPEI that induces necroptosis, targeting the cell membrane. It is noteworthy for its effective induction of membrane damage and DNA degradation [96].

Monoclonal antibody, peptide, and liposome

Antibody-photosensitizer conjugates (APCs) have proved to be effective in addressing certain cases [97,98]. Epidermal growth factor receptor (EGFR), which is usually overexpressed in cancer, and resistance to EGFR monoclonal antibodies can occur in patients with colorectal cancer (CRC) with Kirsten rat sarcoma 2 virus oncogene homolog (KRAS) mutations [99,100]. Ahn et al. developed an APC using cetuximab and Ce6 as the main components, coupled with PEO-PPO-PEO (P123) to enhance the targeting and stability of the conjugate. In in vitro and in vivo assays, significant inhibition of KRAS-mutant tumors was observed, and whole-genome RNA sequencing further confirmed the induction of ICD (Fig. 7a) [101]. Thankarajan et al. combined activatable oxygen heterocyclic xanthene-cyanine PS with trastuzumab to reduce potential side-effects of PDT, creating a cell-internal esterase-activated “switchable” PS, mI2XCy-Ac. In mouse models, no side-effects were detected in the non-activated form, and activation at the tumor site resulted in effective tumor treatment under light exposure (Fig. 7b) [102].Fig. 7 Example diagram of PDT in collaboration with monoclonal antibody and peptide.

Fig. 7

Connecting PS with peptides to target tumors is a common modification strategy [103]. Fang et al. proposed a direct approach, utilizing a peptide targeting glypican-3 (GPC3) connected to Ce6, resulting in conjugate 8b for precise PDT in hepatocellular carcinoma (HCC) (Fig. 7c) [104]. 8b demonstrated high cancer cell selectivity, targeting lysosomes, inducing cell cycle arrest in the S phase, and exhibiting enhanced anti-tumor activity in vitro and in vivo. Qu et al. Qu et al. prepared charge-reversible nanoparticles via the self-assembly of a pro-apoptotic peptide and Ce6. Pro-apoptotic peptides target mitochondrial membranes, block oxygen consumption, and enhance PDT-induced mitochondria-dependent apoptosis. [105]

Most PSs are not optimistic in terms of water solubility, and liposomes, because of their nontoxic nature and amphiphilic properties, are an ideal choice for improving drug delivery efficiency [[106], [107], [108]]. He et al. reported aminopolyacid liposome-encapsulated porphyrin nanoparticles (ePS), which were obtained by incorporating EDTA-hexadecyl amide conjugates into the porphyrin body (Fig. 8a) [109]. These NPs possess activatable PDT and fluorescence. Additionally, the lipid layer increased, porphyrin uptake by 25-fold compared to the rate of porphyrin uptake obtained with conventional delivery, demonstrating excellent therapeutic effects. Ning et al. designed a platelet-derived extracellular vesicle-hybrid liposome drug delivery system (DCHL) that co-delivered chloroperoxidase (CPO) and aggregation-induced emission (AIE) PS DPDPy (Fig. 8b) [110]. After delivery to tumor cells, light induced the release of DPDPy and CPO. DPDPy generates ROS and H2O2, whereas CPO depends on H2O2 to further induce ICD and oxidative stress, synergistically activating the immune system and leading to systemic immunity. Significant inhibition was observed in the distant tumors of the mice. Because of the EPR effect, liposomes serve as an ideal drug carriers, especially in the design of microenvironment-responsive release. However, there remain risks when circulating to other sites, and when using liposomes to deliver PS, attention must be paid to PS dosage and metabolic clearance.Fig. 8 Example diagram of PDT in collaboration with liposome.

Fig. 8

Investigations on APCs is progressing rapidly in experiments, and it is foreseeable that entering clinical applications will become possible. Their applications in cancer are expected to become more diverse, likely involving the discovery of new targets, ideal carrier platforms, and controllable activation. However, this poses higher demands on developers because the addition of more components may lead to toxicity and conflicting effects, necessitating careful consideration.

Combination with other therapeutics

Chemodynamic therapy (CDT) is a tumor microenvironment-responsive therapy [111]. Iron-based (Cu, Mn, and Co) nanomaterials undergo the Fenton reaction with endogenous H2O2, producing hydroxyl radicals (·OH) to selectively damage cancer cells [112]. Fu et al. proposed a multifunctional nano-combination strategy involving synergistic chemotherapy, PDT, and CDT. They utilized a nano-carrier co-assembled with quercetin and betulinic acid for chemotherapy, along with Ce6, and introduced Cu2+ to create CM@OABACe6/Cu NP [113]. Cu2+ consumption of excess intracellular GSH enhanced the PDT efficacy, and excess H2O2 contributed to the CDT effect.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are classical small-molecule drugs that target non-small-cell lung cancer (NSCLC). Yes-associated protein (YAP) has been identified as a key mediator of EGFR-TKI resistance, and inhibiting YAP is considered a rational approach to restoring sensitivity to EGFR-TKI [114,115]. In response to this, Huang proposed a rational “Cocktail therapy,” co-delivering YAP-siRNA, Pyropheophorbide-a (Ppa), and EGFR-TKI gefitinib (Gef) [116]. Intracellular reductive conditions cause disulfide bond cleavage, releasing siRNA and Gef, synergistically blocking the EGFR pathway and suppressing glycolysis, substantially alleviating the hypoxia induced by PDT. Encouraging therapeutic effects have been observed in both gefitinib-resistant NSCLC cells and cells from patient-derived cells.

Apart from the mentioned, researchers have explored numerous synergistic strategies to overcome inherent limitations of PDT or provide more flexible responses to complex cancer situations. Xie et al. combined PDT and PTT, achieving better outcomes in certain tumor conditions [117]. Combining PDT with sonodynamic therapy can mitigate the side effects of light on normal tissues [118]. Gas therapies, represented by H2S and NO, are novel synergistic approaches that can re-sensitize cancer cells, offering flexibility in overcoming resistance [119].

When it comes to synergistic immunotherapeutic strategies based on PDT, it is essential to avoid hasty combinations and instead understand the intrinsic synergistic mechanisms, as chemotherapy often induces immunosuppression. Overly complex structural designs can lead to contradictory effects; therefore, caution is required when designing structures with more than two components. To enhance tumor accumulation, active targeting based on peptides, monoclonal antibodies, and biological membranes is generally more efficient than EPR-mediated passive targeting. However, the challenge lies in efficient large-scale production and purification while maintaining bioactivity, which is critical for clinical translation. Preclinical studies should focus on specific cases and propose customized strategies.

Increasing the monomodal efficiency of PDT

Designing of photosensitizer structure

Relative long excitation wavelengths and tissue safety are commonly referred to as the “Therapeutic window” [120]. Even indocyanine green, a series of BPDIPY molecules, and AIE molecules utilizing conjugated linkage design strategies demonstrate unsatisfactory excitation wavelength and ROS generation rates [[121], [122], [123]].

Xu et al. disclosed a NIR supramolecular PS, RuDA, containing a donor-acceptor (D-A) ligand, which self-assembles in aqueous solution and evidences aggregation-induced high ISC efficiency (Fig. 9a) [124]. The development of NIR-excited PSs is constrained by the “Energy gap law,” which is because of the rapid vibrational relaxation that further limits electron and energy transfer, leading to a reduced rate of ROS production. Zhao et al. employed the “Exciton-vibration decoupling to promote exciton delocalization” method and chose the π-conjugated system hexaazatrinaphthalene (HATN) as the ligand to construct the Ir(III) complexes IrHA1 and IrHA2. Remarkably, IrHA2 exhibited the highest 1O2 quantum yield with 808 nm excitation in its self-aggregated state, making this achievement noteworthy (Fig. 9b) [125].Fig. 9 Structure design example of photosensitizer for enhancing PDT efficiency.

Fig. 9

An illustration of this is BT3 nanoparticles (NPs), grounded in the d-π-A design concept, using benzothiadiazole as the core, introducing cyanide as electron-withdrawing units and self-assembling in water with the addition of PEG. Under 843 nm long-wavelength excitation, excellent photoacoustic imaging and ROS generation are manifested (Fig. 9c) [126]. For the treatment of deep-seated malignant tumors, it is necessary for PS to be responsive to NIR-II lasers and adaptable to hypoxic environments [127,128]. Wen et al. reported three organic-polymer PSs, namely PTS, PTSe and PTTe, which were developed using the d-A strategy. These utilize thiophene, selenophene or tellurophene as electron-donating units and thienoisoindigo as the electron-accepting unit. Notably, they showcased significant type I PDT/photothermal therapy (PTT) effects under 1064 nm (Fig. 9d) [129].

Alleviating hypoxia

The Type I mechanism of PDT, which is independent of oxygen, presents an ideal avenue. However, the slower electron transfer compared with the energy transfer in the Type II mechanism poses a challenge for the development of Type I PS. Nevertheless, several promising explanations have been proposed. Zhao et al. selected a pyrrolidine moiety as an electron-donating group to couple with the bay position of perylene diimide (PDI) in Type I PDT. Utilizing the intramolecular charge transfer effect, the excitation shifts to the NIR region. Modification of the amino groups on both sides improved water solubility. Subsequently, the self-assembly in an aqueous solution resulted in Nano PDIPy, which revealed efficient phototoxicity under hypoxic conditions and prolonged in vivo circulation (Fig. 10a) [130]. Certainly, Zhao et al. introduced the theory of self-assembly-induced exciton delocalization, aiming to diminish the internal recombination energy and exciton binding energy. This theory promotes an efficient charge transfer. Zhao et al. substantiated this concept by developing the photosensitive agent PDIMp and validating the transition from a Type II to I process under self-assembly conditions (Fig. 10b) [131]. Xue et al. developed the soluble perylene monoamide PMIC—NC, featuring tertiary ammonium functional groups at both the amide and peri positions. Under 660 nm laser irradiation, PMIC—NC effectively eliminated tumor cells, triggering a robust ICD response and demonstrating exceptional capabilities against both primary and distant metastatic tumors (Fig. 10c) [132]. Notably, a Type III photosensitive mechanism independent of ROS generation, was predicted. A novel family of photosensitive agents, NBEX, was designed for this mechanism. By targeting cancer cells with elevated RNA levels, NBEX disrupts cellular processes, inducing both destruction and an immune response against tumors [133,134].Fig. 10 Structural design example of photosensitizer for relieving hypoxia.

Fig. 10

Perfluorocarbons (PFCs) as exogenous oxygen carriers represent a direct strategy [135]. Another indirect approach involves suppressing cellular respiration to alleviate hypoxic conditions. Qu et al. designed a peptide and PS assembly, followed by PEG crosslinking. The resulting PDC NPs interrupt mitochondrial respiration, alleviating local hypoxia, and enhancing PDT efficacy [105]. Strategies involving internal oxygen supply, such as hydrogen peroxide enzymes, have also been extensively researched [136,137]. Another intriguing report involves biomimetic red blood cells serving as nanocarriers for oxygen [138]. Targeting abnormal tumor vasculature to overcome hypoxia is explored through solutions like HIF-1 and VEGF [139]. Despite offering rich possibilities, the potential biological safety of these approaches requires careful consideration.

Enhancing targeting and metabolism

Designing PSs with subcellular targeting, tumor-site accumulation, and facile metabolism represents another “green” approach, capable of enhancing therapeutic efficacy with minimal dosage and reducing toxic side-effects [140,141]. Different but enhanced ICD effects can be induced targeting various organelles. For instance, mitochondria are considered targets in many cancers, and mitochondrial oxidative stress has been proven to be as an effective strategy for inducing ICD. In most studies, a positive charge introduced by triphenylphosphonium is utilized to achieve mitochondrial targeting [142]. Subsequently, endoplasmic reticulum (ER) stress is another effective ICD pathway, inducing ROS on the ER membrane. Commonly used targeting groups include toluene-sulfonyl amide and pentafluorophenyl [143]. Moreover, targeting cellular pyroptosis often result in resistance to protective autophagy. Hence, the development of lysosome-targeting PS is necessary [144,145]. The critical role of the cell membrane in maintaining the intracellular environments and communication makes PSs targeting cell membranes exhibit outstanding therapeutic effects (Fig. 11) [96,146].Fig. 11 Illustrative diagram of common strategies for targeting organelles with photosensitizer.

Fig. 11

Sun et al. generated BDPd, an NIR PS containing two lysosome-targeting pyrrole groups, from a BPPDIPY dimer, prepared with a poloxamer. Its mechanism of action involves activating the NLRP3/GSDMD pathway, inducing pyroptosis, presenting ICD markers, and inhibiting autophagy (Fig. 12a) [147]. Liu et al., in addition to the existing PS BDP-15, added an amide-linked pyrrole modification to obtain compound 6, which is targeted to lysosomes and considerably delays tumor growth in vivo at a dose of 30 J/cm (Fig. 12b) [148]. Tang et al. engineered a AIE dimer D1, which features strong intramolecular charge transfer π-conjugated photosensitive luminescent groups connected by an octyl group. D1 exhibits excellent cell-membrane localization, and PDT induces cell pyroptosis, promotes dendritic cell maturation, increases the number of activated T cells, provides systemic immunity, and shows remarkable effectiveness in the “Abscopal effect” (Fig. 12c) [149]. Additionally, PDT indicating cell membrane damage through “Self-feedback” is rarely reported [150]. An ER-targeting Ir(III) PS, Ir1, is designed to address the low functionality of immunogenic activation in oral squamous cell carcinoma. Its hydrophobic long-chain-modified phenanthroline ligand accumulates in the ER, triggering ER stress and further leading to enhanced DAMPs release, inducing ICD reinforcement and eliciting a potent immune response (Fig. 12d) [151]. Zhang et al. fabricated a PS with ER-targeting and efficient imaging capabilities, wherein the nitroreductase-sensitive phenol group alleviated tissue hypoxia [152]. Another direct confirmation that ER stress can induce ICD is the AIE PS DAPASCP-Tos reported by Miao et al. After co-culturing light-treated cancer cells with bone marrow-derived dendritic cells (BMDCs), enhanced maturation and activation of BMDCs were observed, and mice in the in vivo model showed resistance to tumor rechallenge (Fig. 12e) [153]. Yang et al. developed NIR-II-excited therapeutic-diagnostic agents, FE-T NPs, which were responsive to glutathione and released mitochondria-targeting PS. Simultaneously showing mitochondrial targeting and PDT/PTT effects, it reverses the TIME and enhances immunotherapy (Fig. 12f) [154]. Addressing immune escape caused by ER-mitochondria crosstalk, Wang et al. processed the probe THTTPy-PTSA, endowed with ER-targeting properties through the methyl benzenesulfonic acid group. Under light exposure, the converted pyridine group can redirect towards the mitochondria, enhancing ICD mainly due to augmented ER stress (Fig. 12g) [155]. In disturbing cellular redox homeostasis, Ru and Ir have been proven to interfere with photolyzing NADH capabilities [156,157]. The cell nucleus plays a crucial role in cellular fate, making nuclear targeting an ideal approach in anticancer treatment. Development of nucleus-targeting PSs is a promising avenue, as they offer enhanced precision compared with that offered by traditional chemotherapy drugs [158]. Wang et al. adopted a d-A configuration to design a nucleus-targeting AIE PS, MeTPAE [159]. MeTPAE, with triphenylamine as the core, features positively charged pyridine groups at both ends, promoting electrostatic binding with nucleic acids. The third end is substituted with a hydroxamic acid-chelating group to chelate zinc ions in histone deacetylases (HDACs). Experimental verification has demonstrated that MeTPAE has a dual functions in nucleic acid destruction, telomerase inhibition and PDT.Fig. 12 Example of structural design of organelle targeting photosensitizer.

Fig. 12

To expedite clinical translation, an exclusive focus on ROS generation is inadequate, the currently sparse endeavors on drug metabolism necessitates heightened attention [160]. Zhang et al., based on boron dipyrromethene (BODIPY), introduced pyridine groups and TEG chains, reported an ultra-small-sized nano PS demonstrating outstanding tumor-site accumulation and kidney clearance capabilities (Fig. 13a) [161]. The PS FBD developed by Wu et al. indicates excellent anticancer efficiency and can be oxidized in vivo by endogenous ClO− into non-photosensitive FBDO, which is rapidly cleared through urine, minimizing post-PDT side effects (Fig. 13b) [162]. Yuan et al. prepared a supramolecular PS with self-degradation capability, reducing PDT side effects without compromising treatment efficiency (Fig. 13c) [163].Fig. 13 Example of metabolizable photosensitizers in vivo.

Fig. 13

In the aforementioned studies, precise targeting of organelles in PDT can achieve significant effects with small doses. Solely focusing on PDT efficiency, targeting mitochondria is an effective and mature approach. Despite this, for inducing ICD, the ER is an ideal target due to its significant organelle structure and essential role in protein synthesis. ROS-mediated ER stress is more likely to induce CRT and ICD.

In the monomodal treatment of PDT, the primary focus is to regulate the photophysical and chemical properties of the PS, improve targeting and metabolism, and optimizing biosafety. Although there has been extensive research on enhancing ROS production and red-shifted excitation wavelengths, the lack of in vivo metabolic safety assessments remains a key barrier to clinical application. This should be the focus of future research.

Discussion

Photodynamic therapy not only directly damages primary tumors but has also been found to induce distant effects similar to radiotherapy. This is achieved by triggering various ICD effects that activate the immune system. Anti-tumor immunity is considered the most promising approach. Therefore, enhancing PDT-induced ICD and incorporating multi-component synergistic immune activation are the two mainstream strategies for achieving PIT.

Photosensitizer development is influenced by the (1) excitation wavelength, (2) hypoxic conditions, (3) ROS production rate, and (4) targeting, dark toxicity, and metabolic limitations. To address these challenges, strategies based on PS modifications, such as red-shifting excitation wavelengths and Type I photodynamic development, have demonstrated excellent outcomes. More studies have focused on the incorporation of multiple components using nanotechnology-supported delivery systems.

Introducing specific personalized treatment strategies, such as co-delivering YAP-siRNA to overcome resistance in Gefitinib-resistant NSCLC, or introducing Trastuzumab to overcome EGFR resistance and downregulate GSH levels with V9302, holds great promise. The synergistic effect of combining PSs with chemotherapeutic agents such as oxaliplatin or 5-Fu enhances ICD. For severe hypoxia in deep-seated tumors, strategies involve the use of PFC for external oxygen delivery or the inhibition of cellular respiration. To counteract immune escape, the introduction of ICB drugs like NLG-919 proves effective. Delivery systems for non-single components often adopt self-assembly into nano-sized particles, exploiting the EPR effect for tumor site accumulation, as demonstrated with carrier-free self-delivery systems for Ce6 and NLG-919. Targeting peptide conjugation and biomimetic membrane encapsulation have also shown promising prospects as delivery systems.

Despite extensive progress in the basic research on PIT, its translation into clinical applications remains challenging. Firstly, the selection of PSs with good biocompatibility is particularly important, which is critical for moving towards clinical applications. Currently, organic PSs are more promising rather than inorganic and metal-based ones, are more promising, similar to those approved for clinical use. Secondly, synergistic therapies are not merely a straightforward combination. Understanding the related mechanisms is crucial to avoid conflicts and potentially increased toxicity, particularly in studies involving multiple components. Third, in carrier systems, selecting carriers that are metabolically non-toxic is advantageous. The preparation process of multi-component NPs also requires consideration of the deactivation of the active components. Finally, studies on immune activation are mostly limited to in vitro cell or in vivo mouse model studies, with limited exploration in primate models, hence a critical approach to PIT is warranted. In conclusion, cancer PIT may be effective in overcoming the limitations of single therapies, thereby substantially improving treatment outcomes. Current PIT research has focused on reducing irAEs and optimizing biosafety. By thoroughly considering cancer types, genetic factors, and immune properties, the effective integration of current treatment methods and optimization of multimodal tumor suppression holds immense promise.

Funding

We are grateful to the 10.13039/501100001809 National Natural Science Foundation of China (No. 82173852 and No. 81503099 ) for financial aids to this work.

CRediT authorship contribution statement

Deming Zhao: Writing – review & editing, Writing – original draft, Visualization, Conceptualization. Xin Wen: Writing – review & editing, Conceptualization. Jiani Wu: Writing – review & editing, Conceptualization. Feihong Chen: Writing – review & editing, Funding acquisition, Conceptualization.

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.

Acknowledgements

This work was supported by the 10.13039/501100001809 National Natural Science Foundation of China (Grant Nos. 82173852 , 81503099 ).
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References

1 Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries CA Cancer J. Clin. 71 3 2021 209 249 10.3322/caac.21660 33538338
2 Chin A.L. Jiang S. Jang E. Niu L. Li L. Jia X. Tong R. Implantable Optical Fibers for Immunotherapeutics Delivery and Tumor Impedance Measurement Nat. Commun. 12 1 2021 5138 10.1038/s41467-021-25391-z 34446702
3 Lin M.J. Svensson-Arvelund J. Lubitz G.S. Marabelle A. Melero I. Brown B.D. Brody J.D. Cancer Vaccines: The next Immunotherapy Frontier Nat. Cancer 3 8 2022 911 926 10.1038/s43018-022-00418-6 35999309
4 Zheng Y. Zhang Z. Liu Q. Zhao Y. Zheng C. Hao J. Yi K. Wang Y. Wang C. Zhao X. Shi L. Kang C. Liu Y. Multifunctional Nanomodulators Regulate Multiple Pathways To Enhance Antitumor Immunity ACS. Appl. Bio Mater. 3 7 2020 4635 4642 10.1021/acsabm.0c00513
5 Li G. Choi J.E. Kryczek I. Sun Y. Liao P. Li S. Wei S. Grove S. Vatan L. Nelson R. Schaefer G. Allen S.G. Sankar K. Fecher L.A. Mendiratta-Lala M. Frankel T.L. Qin A. Waninger J.J. Tezel A. Alva A. Lao C.D. Ramnath N. Cieslik M. Harms P.W. Green M.D. Chinnaiyan A.M. Zou W. Intersection of Immune and Oncometabolic Pathways Drives Cancer Hyperprogression during Immunotherapy Cancer Cell 41 2 2023 304 322.e7 10.1016/j.ccell.2022.12.008 36638784
6 Xue Y. Che J. Ji X. Li Y. Xie J. Chen X. Recent Advances in Biomaterial-Boosted Adoptive Cell Therapy Chem. Soc. Rev. 51 5 2022 1766 1794 10.1039/d1cs00786f 35170589
7 Topalian S.L. Taube J.M. Anders R.A. Pardoll D.M. Mechanism-Driven Biomarkers to Guide Immune Checkpoint Blockade in Cancer Therapy Nat. Rev. Cancer 16 5 2016 275 287 10.1038/nrc.2016.36 27079802
8 Charneau J. Suzuki T. Shimomura M. Fujinami N. Nakatsura T. Peptide-Based Vaccines for Hepatocellular Carcinoma: A Review of Recent Advances J. HepatoCell Carcinoma 8 2021 1035 1054 10.2147/JHC.S291558 34513746
9 Rotte A. Combination of CTLA-4 and PD-1 Blockers for Treatment of Cancer J. Exp. Clin. Cancer Res. 38 1 2019 255 10.1186/s13046-019-1259-z 31196207
10 Ribas A. Wolchok J.D. Cancer Immunotherapy Using Checkpoint Blockade Science (1979) 359 6382 2018 1350 1355 10.1126/science.aar4060
11 Zhang Y. Zhang Z. The History and Advances in Cancer Immunotherapy: Understanding the Characteristics of Tumor-Infiltrating Immune Cells and Their Therapeutic Implications Cell Mol. Immunol. 17 8 2020 807 821 10.1038/s41423-020-0488-6 32612154
12 Morris E.C. Neelapu S.S. Giavridis T. Sadelain M. Cytokine Release Syndrome and Associated Neurotoxicity in Cancer Immunotherapy Nat. Rev. Immunol. 22 2 2022 85 96 10.1038/s41577-021-00547-6 34002066
13 Zhang Y. Chen J. Shi L. Ma F. Polymeric Nanoparticle-Based Nanovaccines for Cancer Immunotherapy Mater. Horiz. 10 2 2023 361 392 10.1039/d2mh01358d 36541078
14 Moloudi K. Sarbadhikary P. Abrahamse H. George B.P. Understanding the Photodynamic Therapy Induced Bystander and Abscopal Effects: A Review Antioxidants. (Basel) 12 7 2023 1434 10.3390/antiox12071434 37507972
15 Lu Y. Sun W. Du J. Fan J. Peng X. Immuno-Photodynamic Therapy (IPDT): Organic Photosensitizers and Their Application in Cancer Ablation JACS. Au 3 3 2023 682 699 10.1021/jacsau.2c00591 37006765
16 Xi Y. Chen L. Tang J. Yu B. Shen W. Niu X. Amplifying “Eat Me Signal” by Immunogenic Cell Death for Potentiating Cancer Immunotherapy Immunol. Rev. 321 1 2024 94 114 10.1111/imr.13251 37550950
17 Chou W. Sun T. Peng N. Wang Z. Chen D. Qiu H. Zhao H. Photodynamic Therapy-Induced Anti-Tumor Immunity: Influence Factors and Synergistic Enhancement Strategies Pharmaceutics. 15 11 2023 2617 10.3390/pharmaceutics15112617 38004595
18 Mitsunaga M. Ogawa M. Kosaka N. Rosenblum L.T. Choyke P.L. Kobayashi H. Cancer Cell–Selective in Vivo near Infrared Photoimmunotherapy Targeting Specific Membrane Molecules Nat. Med. 17 12 2011 1685 1691 10.1038/nm.2554 22057348
19 Kobayashi H. Choyke P.L. Near-Infrared Photoimmunotherapy of Cancer Acc. Chem. Res. 52 8 2019 2332 2339 10.1021/acs.accounts.9b00273 31335117
20 Mellman I. Chen D.S. Powles T. Turley S.J. The Cancer-Immunity Cycle: Indication, Genotype, and Immunotype Immunity. 56 10 2023 2188 2205 10.1016/j.immuni.2023.09.011 37820582
21 Yang Z. Ma Y. Zhao H. Yuan Y. Kim B.Y.S. Nanotechnology Platforms for Cancer Immunotherapy Wiley. Interdiscip. Rev. Nanomed. Nanobiotechnol. 12 2 2020 e1590 10.1002/wnan.1590 31696664
22 McKenzie B. Valitutti S. Resisting T Cell Attack: Tumor-Cell-Intrinsic Defense and Reparation Mechanisms Trends. Cancer 9 3 2023 198 211 10.1016/j.trecan.2022.12.003 36593148
23 Zhang T. Tai Z. Miao F. Zhang X. Li J. Zhu Q. Wei H. Chen Z. Adoptive Cell Therapy for Solid Tumors beyond CAR-T: Current Challenges and Emerging Therapeutic Advances J. Control Release 368 2024 372 396 10.1016/j.jconrel.2024.02.033 38408567
24 Banstola A. Jeong J.H. Yook S. Immunoadjuvants for Cancer Immunotherapy: A Review of Recent Developments Acta Biomater. 114 2020 16 30 10.1016/j.actbio.2020.07.063 32777293
25 Wang D. Liu B. Zhang Z. Accelerating the Understanding of Cancer Biology through the Lens of Genomics Cell 186 8 2023 1755 1771 10.1016/j.cell.2023.02.015 37059071
26 Greene S. Robbins Y. Mydlarz W. Huynh A. Schmitt N. Friedman J. Horn L.A. Palena C. Schlom J. Maeda D.Y. Zebala J.A. Clavijo P.E. Allen C.T. Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK Cell Immunotherapy in Head and Neck Cancer Models Clin. Cancer Res. 26 6 2020 1420 1431 10.1158/1078-0432.CCR-19-2625 31848188
27 Eccleston A. Suppressing Tumour Treg Cells with a Histone Demethylase Inhibitor Nat. Rev. Drug Discov. 2024 10.1038/d41573-024-00046-y
28 Tie Y. Tang F. Wei Y.Q. Wei X.W. Immunosuppressive Cells in Cancer: Mechanisms and Potential Therapeutic Targets J. Hematol. Oncol. 15 1 2022 61 10.1186/s13045-022-01282-8 35585567
29 Durham B.H. Lopez Rodrigo E. Picarsic J. Abramson D. Rotemberg V. De Munck S. Pannecoucke E. Lu S.X. Pastore A. Yoshimi A. Mandelker D. Ceyhan-Birsoy O. Ulaner G.A. Walsh M. Yabe M. Petrova-Drus K. Arcila M.E. Ladanyi M. Solit D.B. Berger M.F. Hyman D.M. Lacouture M.E. Erickson C. Saganty R. Ki M. Dunkel I.J. Santa-María López V. Mora J. Haroche J. Emile J.F. Decaux O. Geissmann F. Savvides S.N. Drilon A. Diamond E.L. Abdel-Wahab O. Activating Mutations in CSF1R and Additional Receptor Tyrosine Kinases in Histiocytic Neoplasms Nat. Med. 25 12 2019 1839 1842 10.1038/s41591-019-0653-6 31768065
30 Wang F. Fu K. Wang Y. Pan C. Wang X. Liu Z. Yang C. Zheng Y. Li X. Lu Y. To K.K.W. Xia C. Zhang J. Shi Z. Hu Z. Huang M. Fu L. Small-Molecule Agents for Cancer Immunotherapy Acta Pharm. Sin. B 14 3 2024 905 952 10.1016/j.apsb.2023.12.010 38486980
31 Offringa R. Kötzner L. Huck B. Urbahns K. The Expanding Role for Small Molecules in Immuno-Oncology Nat. Rev. Drug Discov. 21 11 2022 821 840 10.1038/s41573-022-00538-9 35982333
32 Chalan P. Di Dalmazi G. Pani F. De Remigis A. Corsello A. Caturegli P. Thyroid Dysfunctions Secondary to Cancer Immunotherapy J. Endocrinol. Invest. 41 6 2018 625 638 10.1007/s40618-017-0778-8 29238906
33 Pitt J.M. Vétizou M. Daillère R. Roberti M.P. Yamazaki T. Routy B. Lepage P. Boneca I.G. Chamaillard M. Kroemer G. Zitvogel L. Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors Immunity. 44 6 2016 1255 1269 10.1016/j.immuni.2016.06.001 27332730
34 Pashootan P. Saadati F. Fahimi H. Rahmati M. Strippoli R. Zarrabi A. Cordani M. Moosavi M.A. Metal-Based Nanoparticles in Cancer Therapy: Exploring Photodynamic Therapy and Its Interplay with Regulated Cell Death Pathways Int. J. Pharm. 649 2024 123622 10.1016/j.ijpharm.2023.123622
35 Donohoe C. Senge M.O. Arnaut L.G. Gomes-da-Silva L.C. Cell Death in Photodynamic Therapy: From Oxidative Stress to Anti-Tumor Immunity Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1872 2 2019 188308 10.1016/j.bbcan.2019.07.003
36 Zeng L. Gupta P. Chen Y. Wang E. Ji L. Chao H. Chen Z.S. The Development of Anticancer Ruthenium(Ii) Complexes: From Single Molecule Compounds to Nanomaterials Chem. Soc. Rev. 46 19 2017 5771 5804 10.1039/c7cs00195a 28654103
37 Lui H. Photodynamic Therapy in Dermatology with Porfimer Sodium and Benzoporphyrin Derivative: An Update Semin. Oncol. 21 6 Suppl 15 1994 11 14
38 Harris F. Pierpoint L. Photodynamic Therapy Based on 5-Aminolevulinic Acid and Its Use as an Antimicrobial Agent Med. Res. Rev. 32 6 2012 1292 1327 10.1002/med.20251 21793017
39 Yano T. Minamide T. Takashima K. Nakajo K. Kadota T. Yoda Y. Clinical Practice of Photodynamic Therapy Using Talaporfin Sodium for Esophageal Cancer J. Clin. Med. 10 13 2021 2785 10.3390/jcm10132785 34202917
40 Bacalbasa N. Balescu I. Diaconu C. Savu C. Savu C. Neacsu A. Belu E. Bratu O. Cretoiu D. Halmaciu I. Iliescu L. Balalau C. Filipescu A. Vilcu M. Brezean I. Utility of Indocyanine Green Injection in Patients with Cervical Cancer besides the Identification of Sentinel Lymph Node (Review) Exp. Ther. Med. 20 4 2020 3523 3527 10.3892/etm.2020.9095 32905080
41 Senge M.O. Brandt J.C. Temoporfin (Foscan®, 5,10,15,20-Tetra(m-Hydroxyphenyl)Chlorin)–a Second-Generation Photosensitizer Photochem. Photobiol. 87 6 2011 1240 1296 10.1111/j.1751-1097.2011.00986.x 21848905
42 Zhang R. Zhu Z. Lv H. Li F. Sun S. Li J. Lee C.S. Immune Checkpoint Blockade Mediated by a Small-Molecule Nanoinhibitor Targeting the PD-1/PD-L1 Pathway Synergizes with Photodynamic Therapy to Elicit Antitumor Immunity and Antimetastatic Effects on Breast Cancer Small. 15 49 2019 e1903881 10.1002/smll.201903881
43 Coleman J. Sjoberg D.D. Demac Q. ODea C. McGill M. Tracey A. Nogueira L. Vickers A. Estes C. Fine S. Akin O. Mulhall J. Sandhu J. Carver B.S. Laudone V.P. Ehdaie B. Scherz A.J. Scardino P.T. Eastham J.A. Phase 2b Trial Results of Padeliporfin (WST11 or Tookad) Vascular-Targeted Photodynamic Therapy for Partial Gland Ablation in Men with Intermediate-Risk Prostate Cancer Journal of Clinical Oncology 2021 10.1200/JCO.2021.39.15_suppl.e17006
44 Marshall J.F. Chan W.S. Hart I.R. Effect of Photodynamic Therapy on Anti-Tumor Immune Defenses: Comparison of the Photosensitizers Hematoporphyrin Derivative and Chloro-Aluminum Sulfonated Phthalocyanine Photochem. Photobiol. 49 5 1989 627 632 10.1111/j.1751-1097.1989.tb08434.x 2755999
45 Roguin L.P. Chiarante N. García Vior M.C. Marino J. Zinc(II) Phthalocyanines as Photosensitizers for Antitumor Photodynamic Therapy Int. J. Biochem. Cell Biol. 114 2019 105575 10.1016/j.biocel.2019.105575
46 Monro S. Colón K.L. Yin H. Roque J. Konda P. Gujar S. Thummel R.P. Lilge L. Cameron C.G. McFarland S.A. Transition Metal Complexes and Photodynamic Therapy from a Tumor-Centered Approach: Challenges, Opportunities, and Highlights from the Development of TLD1433 Chem. Rev. 119 2 2019 797 828 10.1021/acs.chemrev.8b00211 30295467
47 Osuchowski M. Bartusik-Aebisher D. Osuchowski F. Aebisher D. Photodynamic Therapy for Prostate Cancer – A Narrative Review Photodiagnosis. Photodyn. Ther. 33 2021 102158 10.1016/j.pdpdt.2020.102158
48 Miyazaki N.L. Furusawa A. Choyke P.L. Kobayashi H. Review of RM-1929 Near-Infrared Photoimmunotherapy Clinical Efficacy for Unresectable and/or Recurrent Head and Neck Squamous Cell Carcinoma Cancers. (Basel) 15 21 2023 5117 10.3390/cancers15215117 37958293
49 Wang Q. Ju X. Wang J. Fan Y. Ren M. Zhang H. Immunogenic Cell Death in Anticancer Chemotherapy and Its Impact on Clinical Studies Cancer Lett. 438 2018 17 23 10.1016/j.canlet.2018.08.028 30217563
50 Ji J. Xi Y. Zhai G. Multifunctional Biomimetic Nanoplatform Based on Photodynamic Therapy and DNA Repair Intervention for the Synergistic Treatment of Breast Cancer Acta Biomater. 157 2023 551 565 10.1016/j.actbio.2022.12.010 36513248
51 Kang X. Zhang Y. Song J. Wang L. Li W. Qi J. Tang B.Z. A Photo-Triggered Self-Accelerated Nanoplatform for Multifunctional Image-Guided Combination Cancer Immunotherapy Nat. Commun. 14 2023 5216 10.1038/s41467-023-40996-2 37626073
52 Krasnovskaya O.O. Akasov R.A. Spector D.V. Pavlov K.G. Bubley A.A. Kuzmin V.A. Kostyukov A.A. Khaydukov E.V. Lopatukhina E.V. Semkina A.S. Vlasova K.Y. Sypalov S.A. Erofeev A.S. Gorelkin P.V. Vaneev A.N. Nikitina V.N. Skvortsov D.A. Ipatova D.A. Mazur D.M. Zyk N.V. Sakharov D.A. Majouga A.G. Beloglazkina E.K. Photoinduced Reduction of Novel Dual-Action Riboplatin Pt(IV) Prodrug ACS. Appl. Mater. Interfaces. 15 10 2023 12882 12894 10.1021/acsami.3c01771 36854172
53 Sharma P. Siddiqui B.A. Anandhan S. Yadav S.S. Subudhi S.K. Gao J. Goswami S. Allison J.P. The Next Decade of Immune Checkpoint Therapy Cancer Discov. 11 4 2021 838 857 10.1158/2159-8290.CD-20-1680 33811120
54 Blum S.M. Rouhani S.J. Sullivan R.J. Effects of Immune-Related Adverse Events (irAEs) and Their Treatment on Antitumor Immune Responses Immunol. Rev. 318 1 2023 167 178 10.1111/imr.13262 37578634
55 Cina M.L. Venegas J. Young A. Stocking the Toolbox-Using Preclinical Models to Understand the Development and Treatment of Immune Checkpoint Inhibitor-Induced Immune-Related Adverse Events Immunol. Rev. 318 1 2023 110 137 10.1111/imr.13250 37565407
56 Doki Y. Ajani J.A. Kato K. Xu J. Wyrwicz L. Motoyama S. Ogata T. Kawakami H. Hsu C.H. Adenis A. El Hajbi F. Di Bartolomeo M. Braghiroli M.I. Holtved E. Ostoich S.A. Kim H.R. Ueno M. Mansoor W. Yang W.C. Liu T. Bridgewater J. Makino T. Xynos I. Liu X. Lei M. Kondo K. Patel A. Gricar J. Chau I. Kitagawa Y. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma New England Journal of Medicine 386 5 2022 449 462 10.1056/NEJMoa2111380 35108470
57 Altorki N.K. McGraw T.E. Borczuk A.C. Saxena A. Port J.L. Stiles B.M. Lee B.E. Sanfilippo N.J. Scheff R.J. Pua B.B. Gruden J.F. Christos P.J. Spinelli C. Gakuria J. Uppal M. Binder B. Elemento O. Ballman K.V. Formenti S.C. Neoadjuvant Durvalumab with or without Stereotactic Body Radiotherapy in Patients with Early-Stage Non-Small-Cell Lung Cancer: A Single-Centre, Randomised Phase 2 Trial Lancet Oncol. 22 6 2021 824 835 10.1016/S1470-2045(21)00149-2 34015311
58 Li Y. Zhang X. Wan X. Liu X. Pan W. Li N. Tang B. Inducing Endoplasmic Reticulum Stress to Expose Immunogens: A DNA Tetrahedron Nanoregulator for Enhanced Immunotherapy Adv Funct Materials 30 48 2020 2000532 10.1002/adfm.202000532
59 Yang X. Li J. Yu Y. Wang J. Li D. Cao Z. Yang X. Engineering of a Universal Polymeric Nanoparticle Platform to Optimize the PEG Density for Photodynamic Therapy Sci. China Chem. 62 10 2019 1379 1386 10.1007/s11426-019-9505-y
60 Twomey J.D. Zhang B. Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics AAPS. J. 23 2 2021 39 10.1208/s12248-021-00574-0 33677681
61 Lou J. Aragaki M. Bernards N. Kinoshita T. Mo J. Motooka Y. Ishiwata T. Gregor A. Chee T. Chen Z. Chen J. Kaga K. Wakasa S. Zheng G. Yasufuku K. Repeated Porphyrin Lipoprotein-Based Photodynamic Therapy Controls Distant Disease in Mouse Mesothelioma via the Abscopal Effect Nanophotonics. 10 12 2021 3279 3294 10.1515/nanoph-2021-0241 36405502
62 Lou J. Aragaki M. Bernards N. Chee T. Gregor A. Hiraishi Y. Ishiwata T. Leung C. Ding L. Kitazawa S. Koga T. Sata Y. Ogawa H. Chen J. Kato T. Yasufuku K. Zheng G. Repeated Photodynamic Therapy Mediates the Abscopal Effect through Multiple Innate and Adaptive Immune Responses with and without Immune Checkpoint Therapy Biomaterials 292 2023 121918 10.1016/j.biomaterials.2022.121918
63 Heimberger A.B. Lukas R.V. The Kynurenine Pathway Implicated in Patient Delirium: Possible Indications for Indoleamine 2,3 Dioxygenase Inhibitors J. Clin. Invest. 133 2 2023 e164577 10.1172/JCI164577
64 Zheng R.R. Zhao L.P. Yang N. Chen Z.X. Kong R.J. Huang C.Y. Rao X.N. Chen X. Cheng H. Li S.Y. Cascade Immune Activation of Self-Delivery Biomedicine for Photodynamic Immunotherapy Against Metastatic Tumor Small. 19 3 2023 2205694 10.1002/smll.202205694
65 Yan Y. Yao D. Li X. Immunological Mechanism and Clinical Application of PAMP Adjuvants Recent. Pat. AntiCancer Drug Discov. 16 1 2021 30 43 10.2174/1574892816666210201114712 33563182
66 Ong G.H. Lian B.S.X. Kawasaki T. Kawai T. Exploration of Pattern Recognition Receptor Agonists as Candidate Adjuvants Front. Cell Infect. Microbiol. 11 2021 745016 10.3389/fcimb.2021.745016
67 Vollmer J. Krieg A.M. Immunotherapeutic Applications of CpG Oligodeoxynucleotide TLR9 Agonists Adv. Drug Deliv. Rev. 61 3 2009 195 204 10.1016/j.addr.2008.12.008 19211030
68 Allacher P. Baumgartner C.K. Pordes A.G. Ahmad R.U. Schwarz H.P. Reipert B.M. Stimulation and Inhibition of FVIII-Specific Memory B-Cell Responses by CpG-B (ODN 1826), a Ligand for Toll-like Receptor 9 Blood 117 1 2011 259 267 10.1182/blood-2010-06-289009 20889922
69 Wei J. Wu D. Zhao S. Shao Y. Xia Y. Ni D. Qiu X. Zhang J. Chen J. Meng F. Zhong Z. Immunotherapy of Malignant Glioma by Noninvasive Administration of TLR9 Agonist CpG Nano-Immunoadjuvant Adv. Sci. (Weinh) 9 13 2022 e2103689 10.1002/advs.202103689
70 Meng Z. Wang T. Hu Y. Ouyang H. Wang Q. Wu M. Zhou J. Lou X. Wang S. Dai J. Xia F. Macrophage Membrane-Camouflaged Aggregation-Induced Emission Nanoparticles Enhance Photodynamic-Immunotherapy to Delay Postoperative Tumor Recurrence Adv. Healthc. Mater. 13 4 2024 e2302156 10.1002/adhm.202302156
71 Liu Y.B. Chen X.Y. Yu B.X. Cen Y. Huang C.Y. Yan M.Y. Liu Q.Q. Zhang W. Li S.Y. Tang Y.Z. Chimeric Peptide-Engineered Self-Delivery Nanomedicine for Photodynamic-Triggered Breast Cancer Immunotherapy by Macrophage Polarization Small 20 22 2024 e2309994 10.1002/smll.202309994
72 Yu Q. Li X. Wang J. Guo L. Huang L. Gao W. Recent Advances in Reprogramming Strategy of Tumor Microenvironment for Rejuvenating Photosensitizers-Mediated Photodynamic Therapy Small 20 16 2024 e2305708 10.1002/smll.202305708
73 Liu Y. Li C. Lu Y. Liu C. Yang W. Tumor Microenvironment-Mediated Immune Tolerance in Development and Treatment of Gastric Cancer Front. Immunol. 13 2022 1016817 10.3389/fimmu.2022.1016817
74 Zhao L. Rao X. Zheng R. Huang C. Kong R. Yu X. Cheng H. Li S. Targeting Glutamine Metabolism with Photodynamic Immunotherapy for Metastatic Tumor Eradication Journal of Controlled Release 357 2023 460 471 10.1016/j.jconrel.2023.04.027 37068523
75 Galstyan A. Markman J.L. Shatalova E.S. Chiechi A. Korman A.J. Patil R. Klymyshyn D. Tourtellotte W.G. Israel L.L. Braubach O. Ljubimov V.A. Mashouf L.A. Ramesh A. Grodzinski Z.B. Penichet M.L. Black K.L. Holler E. Sun T. Ding H. Ljubimov A.V. Ljubimova J.Y. Blood-Brain Barrier Permeable Nano Immunoconjugates Induce Local Immune Responses for Glioma Therapy Nat. Commun. 10 1 2019 3850 10.1038/s41467-019-11719-3 31462642
76 Lei K. Kurum A. Kaynak M. Bonati L. Han Y. Cencen V. Gao M. Xie Y.Q. Guo Y. Hannebelle M.T.M. Wu Y. Zhou G. Guo M. Fantner G.E. Sakar M.S. Tang L. Cancer-Cell Stiffening via Cholesterol Depletion Enhances Adoptive T-Cell Immunotherapy Nat. Biomed. Eng. 5 12 2021 1411 1425 10.1038/s41551-021-00826-6 34873307
77 Huang B. Song B.L. Xu C. Cholesterol Metabolism in Cancer: Mechanisms and Therapeutic Opportunities Nat. Metab. 2 2 2020 132 141 10.1038/s42255-020-0174-0 32694690
78 Liu X. Zhao Z. Sun X. Wang J. Yi W. Wang D. Li Y. Blocking Cholesterol Metabolism with Tumor-Penetrable Nanovesicles to Improve Photodynamic Cancer Immunotherapy Small. Methods 7 5 2023 e2200898 10.1002/smtd.202200898
79 Vaupel P. Schmidberger H. Mayer A. The Warburg Effect: Essential Part of Metabolic Reprogramming and Central Contributor to Cancer Progression Int. J. Radiat. Biol. 95 7 2019 912 919 10.1080/09553002.2019.1589653 30822194
80 Su Y. Lu K. Huang Y. Zhang J. Sun X. Peng J. Zhou Y. Zhao L. Targeting Warburg Effect to Rescue the Suffocated Photodynamic Therapy: A Cancer-Specific Solution Biomaterials 294 2023 122017 10.1016/j.biomaterials.2023.122017
81 Wang L. Yu J. Fordjour P.A. Xing X. Gao H. Li Y. Li L. Zhu Y. Gao X. Fan G. Danshen Injection Prevents Heart Failure by Attenuating Post-Infarct Remodeling J. Ethnopharmacol. 205 2017 22 32 10.1016/j.jep.2017.04.027 28465251
82 Kumari P. Jain S. Ghosh B. Zorin V. Biswas S. Polylactide-Based Block Copolymeric Micelles Loaded with Chlorin E6 for Photodynamic Therapy: In Vitro Evaluation in Monolayer and 3D Spheroid Models Mol. Pharm. 14 11 2017 3789 3800 10.1021/acs.molpharmaceut.7b00548 28969421
83 Wan J. Zhang X. Tang D. Liu T. Xiao H. Biodegradable NIR-II Pseudo Conjugate Polymeric Nanoparticles Amplify Photodynamic Immunotherapy via Alleviation of Tumor Hypoxia and Tumor-Associated Macrophage Reprogramming Adv. Mater. 35 31 2023 e2209799 10.1002/adma.202209799
84 Zhao L.P. Zheng R.R. Kong R.J. Huang C.Y. Rao X.N. Yang N. Chen A.L. Yu X.Y. Cheng H. Li S.Y. Self-Delivery Ternary Bioregulators for Photodynamic Amplified Immunotherapy by Tumor Microenvironment Reprogramming ACS. Nano 16 1 2022 1182 1197 10.1021/acsnano.1c08978 35023720
85 Alzeibak R. Mishchenko T.A. Shilyagina N.Y. Balalaeva I.V. Vedunova M.V. Krysko D.V. Targeting Immunogenic Cancer Cell Death by Photodynamic Therapy: Past, Present and Future J. ImmunOther Cancer 9 1 2021 e001926 10.1136/jitc-2020-001926
86 Ding J. Wang K. Liu W. She Y. Sun Q. Shi J. Sun H. Wang D.C. Shao F. Pore-Forming Activity and Structural Autoinhibition of the Gasdermin Family Nature 535 7610 2016 111 116 10.1038/nature18590 27281216
87 Yu Z. Cao W. Han C. Wang Z. Qiu Y. Wang J. Wei M. Wang J. Zhang S. Liu S. Mo S. Chen J. Biomimetic Metal-Organic Framework Nanoparticles for Synergistic Combining of SDT-Chemotherapy Induce Pyroptosis in Gastric Cancer Front. Bioeng. Biotechnol. 10 2022 796820 10.3389/fbioe.2022.796820
88 Ding F. Liu J. Ai K. Xu C. Mao X. Liu Z. Xiao H. Simultaneous Activation of Pyroptosis and cGAS-STING Pathway with Epigenetic/ Photodynamic Nanotheranostic for Enhanced Tumor Photoimmunotherapy Adv. Mater. 36 7 2024 e2306419 10.1002/adma.202306419
89 Shishido Y. Amisaki M. Matsumi Y. Yakura H. Nakayama Y. Miyauchi W. Miyatani K. Matsunaga T. Hanaki T. Kihara K. Yamamoto M. Tokuyasu N. Takano S. Sakamoto T. Honjo S. Hasegawa T. Fujiwara Y. Antitumor Effect of 5-Aminolevulinic Acid Through Ferroptosis in Esophageal Squamous Cell Carcinoma Ann. Surg. Oncol. 28 7 2021 3996 4006 10.1245/s10434-020-09334-4 33210267
90 Kojima Y. Tanaka M. Sasaki M. Ozeki K. Shimura T. Kubota E. Kataoka H. Induction of Ferroptosis by Photodynamic Therapy and Enhancement of Antitumor Effect with Ferroptosis Inducers J. Gastroenterol. 2023 10.1007/s00535-023-02054-y
91 Zhou Y. Chen K. Lin W.K. Liu J. Kang W. Zhang Y. Yang R. Jin L. Cheng Y. Xu A. Wang W. Photo-Enhanced Synergistic Induction of Ferroptosis for Anti-Cancer Immunotherapy Adv. Healthc. Mater. 12 27 2023 2300994 10.1002/adhm.202300994
92 Fang L. Han M. Zhang Y. Song Y. Liu B. Cai M. Jiang M. Hu L. Zheng R. Lian X. Yan F. Huang K. Feng S. Single Component Organic Photosensitizer with NIR-I Emission Realizing Type-I Photodynamic and GSH-Depletion Caused Ferroptosis Synergistic Theranostics Adv. Healthc. Mater. 12 21 2023 2300134 10.1002/adhm.202300134
93 Degterev A. Huang Z. Boyce M. Li Y. Jagtap P. Mizushima N. Cuny G.D. Mitchison T.J. Moskowitz M.A. Yuan J. Chemical Inhibitor of Nonapoptotic Cell Death with Therapeutic Potential for Ischemic Brain Injury Nat. Chem. Biol. 1 2 2005 112 119 10.1038/nchembio711 16408008
94 Coupienne I. Fettweis G. Rubio N. Agostinis P. Piette J. 5-ALA-PDT Induces RIP3-Dependent Necrosis in Glioblastoma Photochem. Photobiol. Sci. 10 12 2011 1868 1878 10.1039/c1pp05213f 22033613
95 Zhang Y. Cheung Y.K. Ng D.K.P. Fong W.P. Immunogenic Necroptosis in the Anti-Tumor Photodynamic Action of BAM-SiPc, a Silicon(IV) Phthalocyanine-Based Photosensitizer Cancer Immunol. Immunther. 70 2 2021 485 495 10.1007/s00262-020-02700-x
96 Niu N. Yu Y. Zhang Z. Kang M. Wang L. Zhao Z. Wang D. Tang B.Z. A Cell Membrane-Targeting AIE Photosensitizer as a Necroptosis Inducer for Boosting Cancer Theranostics Chem. Sci. 13 20 2022 5929 5937 10.1039/D2SC01260J 35685806
97 Fu Z. Li S. Han S. Shi C. Zhang Y. Antibody Drug Conjugate: The “Biological Missile” for Targeted Cancer Therapy Signal. Transduct. Target. Ther. 7 1 2022 93 10.1038/s41392-022-00947-7 35318309
98 Li X. Lovell J.F. Yoon J. Chen X. Clinical Development and Potential of Photothermal and Photodynamic Therapies for Cancer Nat. Rev. Clin. Oncol. 17 11 2020 657 674 10.1038/s41571-020-0410-2 32699309
99 Chen W. Jiang J. Gong L. Shu Z. Xiang D. Zhang X. Bi K. Diao H. Hepatitis B Virus P Protein Initiates Glycolytic Bypass in HBV-Related Hepatocellular Carcinoma via a FOXO3/miRNA-30b-5p/MINPP1 Axis J. Exp. Clin. Cancer Res. 40 1 2021 1 10.1186/s13046-020-01803-8 33390177
100 Normanno N. Tejpar S. Morgillo F. De Luca A. Van Cutsem E. Ciardiello F. Implications for KRAS Status and EGFR-Targeted Therapies in Metastatic CRC Nat. Rev. Clin. Oncol. 6 9 2009 519 527 10.1038/nrclinonc.2009.111 19636327
101 Ahn M. Lee T. Kim K.S. Lee S. Na K. Synergistic Approach of Antibody-Photosensitizer Conjugate Independent of KRAS-Mutation and Its Downstream Blockade Pathway in Colorectal Cancer Adv. Healthc. Mater. 12 31 2023 2302374 10.1002/adhm.202302374
102 Thankarajan E. Tuchinsky H. Aviel-Ronen S. Bazylevich A. Gellerman G. Patsenker L. Antibody Guided Activatable NIR Photosensitizing System for Fluorescently Monitored Photodynamic Therapy with Reduced Side Effects Journal of Controlled Release 343 2022 506 517 10.1016/j.jconrel.2022.02.008 35150812
103 Yuan Y. Diao S. Ni X. Zhang D. Yi W. Jian C. Hu X. Li D. Yu A. Zhou W. Fan Q. Peptide-Based Semiconducting Polymer Nanoparticles for Osteosarcoma-Targeted NIR-II Fluorescence/NIR-I Photoacoustic Dual-Model Imaging and Photothermal/Photodynamic Therapies J. Nanobiotechnology. 20 1 2022 44 10.1186/s12951-022-01249-4 35062957
104 Fang Y. Ma H. Zhang X. Zhang P. Li Y. He S. Sheng C. Dong G. Smart Glypican-3-Targeting Peptide–Chlorin E6 Conjugates for Targeted Photodynamic Therapy of Hepatocellular Carcinoma Eur. J. Med. Chem. 264 2024 116047 10.1016/j.ejmech.2023.116047
105 Qu H. Chen H. Cheng W. Pan Y. Duan Z. Wang Y. Liang X.J. Xue X. Charge-Reversible Crosslinked Nanoparticle for pro-Apoptotic Peptide Delivery and Synergistic Photodynamic Cancer Therapy Nano Res. 2023 10.1007/s12274-023-5912-7
106 Fahmy S.A. Azzazy H.M.E.S. Schaefer J. Liposome Photosensitizer Formulations for Effective Cancer Photodynamic Therapy Pharmaceutics. 13 9 2021 1345 10.3390/pharmaceutics13091345 34575424
107 Moghassemi S. Dadashzadeh A. Azevedo R.B. Feron O. Amorim C.A. Photodynamic Cancer Therapy Using Liposomes as an Advanced Vesicular Photosensitizer Delivery System J. Control Release 339 2021 75 90 10.1016/j.jconrel.2021.09.024 34562540
108 Cheng X. Gao J. Ding Y. Lu Y. Wei Q. Cui D. Fan J. Li X. Zhu E. Lu Y. Wu Q. Li L. Huang W. Multi-Functional Liposome: A Powerful Theranostic Nano-Platform Enhancing Photodynamic Therapy Adv. Sci. (Weinh) 8 16 2021 e2100876 10.1002/advs.202100876
109 Ho T. Guidolin K. Makky A. Valic M. Ding L. Bu J. Zheng M. Cheng M.H.Y. Yau J. Chen J. Zheng G. Novel Strategy to Drive the Intracellular Uptake of Lipid Nanoparticles for Photodynamic Therapy Angew. Chem. Int. Ed. Engl. 62 16 2023 e202218218 10.1002/anie.202218218
110 Ning S. Zhang X. Suo M. Lyu M. Pan Y. Jiang Y. Yang H. Yip Lam J.W. Zhang T. Pan L. Tang B.Z. Platelet-Derived Exosomes Hybrid Liposomes Facilitate Uninterrupted Singlet Oxygen Generation to Enhance Breast Cancer Immunotherapy Cell Reports Physical Science 4 7 2023 101505 10.1016/j.xcrp.2023.101505
111 Zhang C. Bu W. Ni D. Zhang S. Li Q. Yao Z. Zhang J. Yao H. Wang Z. Shi J. Synthesis of Iron Nanometallic Glasses and Their Application in Cancer Therapy by a Localized Fenton Reaction Angew. Chem. Int. Ed. Engl. 55 6 2016 2101 2106 10.1002/anie.201510031 26836344
112 Zhao P. Li H. Bu W. A Forward Vision for Chemodynamic Therapy: Issues and Opportunities Angewandte Chemie International Edition 62 7 2023 e202210415 10.1002/anie.202210415
113 Fu S. Wang M. Li B. Li X. Cheng J. Zhao H. Zhang H. Dong A. Lu W. Yang X. Bionic Natural Small Molecule Co-Assemblies towards Targeted and Synergistic Chemo/PDT/CDT Biomater. Res. 27 2023 43 10.1186/s40824-023-00380-z 37161611
114 Okura N. Nishioka N. Yamada T. Taniguchi H. Tanimura K. Katayama Y. Yoshimura A. Watanabe S. Kikuchi T. Shiotsu S. Kitazaki T. Nishiyama A. Iwasaku M. Kaneko Y. Uchino J. Uehara H. Horinaka M. Sakai T. Tanaka K. Kozaki R. Yano S. Takayama K. ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in EGFR-Mutated Non-Small Cell Lung Cancer Clin. Cancer Res. 26 9 2020 2244 2256 10.1158/1078-0432.CCR-19-2321 31953310
115 Nilsson M.B. Sun H. Robichaux J. Pfeifer M. McDermott U. Travers J. Diao L. Xi Y. Tong P. Shen L. Hofstad M. Kawakami M. Le X. Liu X. Fan Y. Poteete A. Hu L. Negrao M.V. Tran H. Dmitrovsky E. Peng D. Gibbons D.L. Wang J. Heymach J.V. A YAP/FOXM1 Axis Mediates EMT-Associated EGFR Inhibitor Resistance and Increased Expression of Spindle Assembly Checkpoint Components Sci. Transl. Med. 12 559 2020 eaaz4589 10.1126/scitranslmed.aaz4589 32878980
116 Huang J. Zhuang C. Chen J. Chen X. Li X. Zhang T. Wang B. Feng Q. Zheng X. Gong M. Gong Q. Xiao K. Luo K. Li W. Targeted Drug/Gene/Photodynamic Therapy via a Stimuli-Responsive Dendritic-Polymer-Based Nanococktail for Treatment of EGFR-TKI-Resistant Non-Small-Cell Lung Cancer Advanced Materials 34 27 2022 2201516 10.1002/adma.202201516
117 Xie H. Bi Z. Yin J. Li Z. Hu L. Zhang C. Zhang J. Lam J.W.Y. Zhang P. Kwok R.T.K. Li K. Tang B.Z. Design of One-for-All Near-Infrared Aggregation-Induced Emission Nanoaggregates for Boosting Theranostic Efficacy ACS. Nano 17 5 2023 4591 4600 10.1021/acsnano.2c10661 36857475
118 Hu H. Zhao J. Ma K. Wang J. Wang X. Mao T. Xiang C. Luo H. Cheng Y. Yu M. Qin Y. Yang K. Li Q. Sun Y. Wang S. Sonodynamic Therapy Combined with Phototherapy: Novel Synergistic Strategy with Superior Efficacy for Antitumor and Antiinfection Therapy J. Control Release 359 2023 188 205 10.1016/j.jconrel.2023.05.041 37286136
119 Yan Z. Liu Z. Zhang H. Guan X. Xu H. Zhang J. Zhao Q. Wang S. Current Trends in Gas-Synergized Phototherapy for Improved Antitumor Theranostics Acta Biomater. 174 2024 1 25 10.1016/j.actbio.2023.12.012 38092250
120 Yan Q. Yao R. Li G. Guo J. Zhao B. Li J. Hang R. Wang H. Enhanced π-Conjugation in Hybridized Local and Charge Transfer State by Intramolecular Hydrogen Bonding to Construct Efficient Red Emitters for OLEDs and Cellular Imaging Dyes and Pigments 215 2023 111290 10.1016/j.dyepig.2023.111290
121 Chen J. Qi C. Zhang Y. Zhang Q. Tu J. Photothermal/Lysozyme-Catalyzed Hydrolysis Dual-Modality Therapy via Halloysite Nanotube-Based Platform for Effective Bacterial Eradication Int. J. Biol. Macromol. 240 2023 124530 10.1016/j.ijbiomac.2023.124530
122 Ding Y. Pan Q. Gao W. Pu Y. Luo K. He B. Reactive Oxygen Species-Upregulating Nanomedicines towards Enhanced Cancer Therapy Biomater. Sci. 11 4 2023 1182 1214 10.1039/D2BM01833K 36606593
123 Alimu G. Yan T. Zhu L. Du Z. Ma R. Fan H. Chen S. Alifu N. Zhang X. Liposomes Loaded with Dual Clinical Photosensitizers for Enhanced Photodynamic Therapy of Cervical Cancer RSC. Adv. 13 6 2023 3459 3467 10.1039/D2RA03055A 36756546
124 Xu G. Li C. Chi C. Wu L. Sun Y. Zhao J. Xia X.H. Gou S.A Supramolecular Photosensitizer Derived from an Arene-Ru(II) Complex Self-Assembly for NIR Activated Photodynamic and Photothermal Therapy Nat. Commun. 13 2022 3064 10.1038/s41467-022-30721-w 35654794
125 Zhao J. Gao Y. Huang R. Chi C. Sun Y. Xu G. Xia X.H. Gou S. Design of Near-Infrared-Triggered Metallo-Photosensitizers via a Self-Assembly-Induced Vibronic Decoupling Strategy J. Am. Chem. Soc. 145 21 2023 11633 11642 10.1021/jacs.3c01645 37203139
126 Wan Y. Lu G. Wei W.C. Huang Y.H. Li S. Chen J.X. Cui X. Xiao Y.F. Li X. Liu Y. Meng X.M. Wang P. Xie H.Y. Zhang J. Wong K.T. Lee C.S. Stable Organic Photosensitizer Nanoparticles with Absorption Peak beyond 800 Nanometers and High Reactive Oxygen Species Yield for Multimodality Phototheranostics ACS. Nano 14 8 2020 9917 9928 10.1021/acsnano.0c02767 32706236
127 Li J. Pu K. Development of Organic Semiconducting Materials for Deep-Tissue Optical Imaging, Phototherapy and Photoactivation Chem. Soc. Rev. 48 1 2019 38 71 10.1039/c8cs00001h 30387803
128 He S. Song J. Qu J. Cheng Z. Crucial Breakthrough of Second Near-Infrared Biological Window Fluorophores: Design and Synthesis toward Multimodal Imaging and Theranostics Chem. Soc. Rev. 47 12 2018 4258 4278 10.1039/c8cs00234g 29725670
129 Wen K. Tan H. Peng Q. Chen H. Ma H. Wang L. Peng A. Shi Q. Cai X. Huang H. Achieving Efficient NIR-II Type-I Photosensitizers for Photodynamic/Photothermal Therapy upon Regulating Chalcogen Elements Advanced Materials 34 7 2022 2108146 10.1002/adma.202108146
130 Zhao J. Huang R. Gao Y. Xu J. Sun Y. Bao J. Fang L. Gou S. Realizing Near-Infrared (NIR)-Triggered Type-I PDT and PTT by Maximizing the Electronic Exchange Energy of Perylene Diimide-Based Photosensitizers ACS Materials Lett 5 6 2023 1752 1759 10.1021/acsmaterialslett.3c00436
131 Fang L. Huang R. Gong W. Ji Y. Sun Y. Gou S. Zhao J. A Self-Assembly-Induced Exciton Delocalization Strategy for Converting a Perylene Diimide Derivative from a Type-II to Type-I Photosensitizer Small 20 12 2024 e2307414 10.1002/smll.202307414
132 Lou X. Wang H. Liu Y. Huang Y. Liu Z. Zhang W. Wang T. Perylene-Based Reactive Oxygen Species Supergenerator for Immunogenic Photochemotherapy against Hypoxic Tumors Angewandte Chemie International Edition 62 11 2023 e202214586 10.1002/anie.202214586
133 Yao Q. Fan J. Long S. Zhao X. Li H. Du J. Shao K. Peng X. The Concept and Examples of Type-III Photosensitizers for Cancer Photodynamic Therapy Chem. 8 1 2022 197 209 10.1016/j.chempr.2021.10.006
134 Allison R.R. Sibata C.H. Oncologic Photodynamic Therapy Photosensitizers: A Clinical Review Photodiagnosis. Photodyn. Ther. 7 2 2010 61 75 10.1016/j.pdpdt.2010.02.001 20510301
135 Zhang Y. Liao Y. Tang Q. Lin J. Huang P. Biomimetic Nanoemulsion for Synergistic Photodynamic-Immunotherapy Against Hypoxic Breast Tumor Angewandte Chemie 133 19 2021 10742 10748 10.1002/ange.202015590
136 Shi C. Li M. Zhang Z. Yao Q. Shao K. Xu F. Xu N. Li H. Fan J. Sun W. Du J. Long S. Wang J. Peng X. Catalase-Based Liposomal for Reversing Immunosuppressive Tumor Microenvironment and Enhanced Cancer Chemo-Photodynamic Therapy Biomaterials 233 2020 119755 10.1016/j.biomaterials.2020.119755
137 Zhang J. Li Z. Liu L. Li L. Zhang L. Wang Y. Zhao J. Self-Assembly Catalase Nanocomplex Conveyed by Bacterial Vesicles for Oxygenated Photodynamic Therapy and Tumor Immunotherapy Int. J. Nanomedicine 17 2022 1971 1985 10.2147/IJN.S353330 35530972
138 Shao J. Pijpers I.A.B. Cao S. Williams D.S. Yan X. Li J. Abdelmohsen L.K.E.A. van Hest J.C.M. Biomorphic Engineering of Multifunctional Polylactide Stomatocytes toward Therapeutic Nano-Red Blood Cells Advanced Science 6 5 2019 1801678 10.1002/advs.201801678
139 Jung E. Kwon S. Song N. Kim N. Jo H. Yang M. Park S. Kim C. Lee D. Tumor-Targeted Redox-Regulating and Antiangiogenic Phototherapeutics Nanoassemblies for Self-Boosting Phototherapy Biomaterials 298 2023 122127 10.1016/j.biomaterials.2023.122127
140 Wang R. Li X. Yoon J. Organelle-Targeted Photosensitizers for Precision Photodynamic Therapy ACS Appl. Mater. Interfaces 13 17 2021 19543 19571 10.1021/acsami.1c02019 33900741
141 Bacellar I.O.L. Tsubone T.M. Pavani C. Baptista M.S. Photodynamic Efficiency: From Molecular Photochemistry to Cell Death Int. J. Mol. Sci. 16 9 2015 20523 20559 10.3390/ijms160920523 26334268
142 Zielonka J. Joseph J. Sikora A. Hardy M. Ouari O. Vasquez-Vivar J. Cheng G. Lopez M. Kalyanaraman B. Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications Chem. Rev. 117 15 2017 10043 10120 10.1021/acs.chemrev.7b00042 28654243
143 Ghosh C. Nandi A. Basu S. Supramolecular Self-Assembly of Triazine-Based Small Molecules: Targeting the Endoplasmic Reticulum in Cancer Cells Nanoscale 11 7 2019 3326 3335 10.1039/c8nr08682f 30724283
144 Zeng S. Chen C. Zhang L. Liu X. Qian M. Cui H. Wang J. Chen Q. Peng X. Activation of Pyroptosis by Specific Organelle-Targeting Photodynamic Therapy to Amplify Immunogenic Cell Death for Anti-Tumor Immunotherapy Bioact. Mater. 25 2022 580 593 10.1016/j.bioactmat.2022.07.016 37056275
145 Li Y. Han W. Gong D. Luo T. Fan Y. Mao J. Qin W. Lin W. A Self-Assembled Nanophotosensitizer Targets Lysosomes and Induces Lysosomal Membrane Permeabilization to Enhance Photodynamic Therapy Chem. Sci. 14 19 2023 5106 5115 10.1039/d3sc00455d 37206384
146 Nakajima K. Takakura H. Shimizu Y. Ogawa M. Changes in Plasma Membrane Damage Inducing Cell Death after Treatment with Near-Infrared Photoimmunotherapy Cancer Sci. 109 9 2018 2889 2896 10.1111/cas.13713 29949672
147 Sun Q. Yang J. Wu Q. Shen W. Yang Y. Yin D. Targeting Lysosome for Enhanced Cancer Photodynamic/Photothermal Therapy in a “One Stone Two Birds” Pattern ACS Appl. Mater. Interfaces 2023 10.1021/acsami.3c13162
148 Liu C. Ji X. Yu Z. Zhang S. Zhang R. Zhao W. Dong X. Discovery of Subcellular-Targeted Aza-BODIPY Photosensitizers for Efficient Photodynamic Antitumor Therapy J. Med. Chem. 66 11 2023 7205 7220 10.1021/acs.jmedchem.2c01653 37204432
149 Tang Y. Bisoyi H.K. Chen X.M. Liu Z. Chen X. Zhang S. Li Q. Pyroptosis-Mediated Synergistic Photodynamic and Photothermal Immunotherapy Enabled by a Tumor-Membrane-Targeted Photosensitive Dimer Advanced Materials 35 25 2023 2300232 10.1002/adma.202300232
150 Yang L. Chen Q. Gan S. Huang C. Zhang H. Sun H. Rational Design of Self-Reporting Photosensitizers for Cell Membrane-Targeted Photodynamic Therapy Anal. Chem. 95 32 2023 11988 11996 10.1021/acs.analchem.3c01659 37530604
151 Zhou J.Y. Shen Q.H. Hong X.J. Zhang W.Y. Su Q. Li W.G. Cheng B. Tan C.P. Wu T. Synergization of an Endoplasmic Reticulum-Targeted Iridium(III) Photosensitizer with PD-L1 Inhibitor for Oral Squamous Cell Carcinoma Immunotherapy Chemical Engineering Journal 474 2023 145516 10.1016/j.cej.2023.145516
152 Zhang J. Zhang Y. Zhang H. Zhai W. Shi X. Li C. A Hypoxia-Activatable Theranostic Agent with Intrinsic Endoplasmic Reticulum Affinity and Type-I Photosensitivity J. Mater. Chem. B 11 18 2023 4102 4110 10.1039/D3TB00328K 37165899
153 Miao Z. Li J. Zeng S. Lv Y. Jia S. Ding D. Li W. Liu Q. Endoplasmic Reticulum-Targeting AIE Photosensitizers to Boost Immunogenic Cell Death for Immunotherapy of Bladder Carcinoma ACS. Appl. Mater. Interfaces. 2023 10.1021/acsami.3c14068
154 Yang S. Sun B. Liu F. Li N. Wang M. Wu P. Wu G. Fang H. He Y. Zhou W. Xiao H. Tan X. Tang L. Zhu S. Yang Q. NIR-II Imaging-Guided Mitochondrial-Targeting Organic Nanoparticles for Multimodal Synergistic Tumor Therapy Small. 19 26 2023 2207995 10.1002/smll.202207995
155 Wang X. Qian J. Yang Z. Song Y. Pan W. Ye Y. Qin X. Yan X. Huang X. Wang X. Gao M. Zhang Y. Photodynamic Modulation of Endoplasmic Reticulum and Mitochondria Network Boosted Cancer Immunotherapy Adv. Mater. 36 4 2024 e2310964 10.1002/adma.202310964
156 Han G. Li G. Huang J. Han C. Turro C. Sun Y. Two-Photon-Absorbing Ruthenium Complexes Enable near Infrared Light-Driven Photocatalysis Nat. Commun. 13 1 2022 2288 10.1038/s41467-022-29981-3 35484148
157 Zhong M. He J. Zhang B. Liu Q. Fang J. Mitochondria-Targeted Iridium-Based Photosensitizers Enhancing Photodynamic Therapy Effect by Disturbing Cellular Redox Balance Free Radical Biology and Medicine 195 2023 121 131 10.1016/j.freeradbiomed.2022.12.091 36581057
158 Wan G. Cheng Y. Song J. Chen Q. Chen B. Liu Y. Ji S. Chen H. Wang Y. Nucleus-Targeting near-Infrared Nanoparticles Based on TAT Peptide-Conjugated IR780 for Photo-Chemotherapy of Breast Cancer Chemical Engineering Journal 380 2020 122458 10.1016/j.cej.2019.122458
159 Wang K.N. Liu L.Y. Mao D. Hou M.X. Tan C.P. Mao Z.W. Liu B. A Nuclear-Targeted AIE Photosensitizer for Enzyme Inhibition and Photosensitization in Cancer Cell Ablation Angewandte Chemie International Edition 61 15 2022 e202114600 10.1002/anie.202114600
160 Li M. Xiong T. Du J. Tian R. Xiao M. Guo L. Long S. Fan J. Sun W. Shao K. Song X. Foley J.W. Peng X. Superoxide Radical Photogenerator with Amplification Effect: Surmounting the Achilles’ Heels of Photodynamic Oncotherapy J. Am. Chem. Soc. 141 6 2019 2695 2702 10.1021/jacs.8b13141 30652866
161 Zhang D. Teng K.X. Zhao L. Niu L.Y. Yang Q.Z. Ultra-Small Nano-Assemblies as Tumor-Targeted and Renal Clearable Theranostic Agent for Photodynamic Therapy Advanced Materials 35 19 2023 2209789 10.1002/adma.202209789
162 Wu W. Shi L. Duan Y. Xu S. Gao X. Zhu X. Liu B. Metabolizable Photosensitizer with Aggregation-Induced Emission for Photodynamic Therapy Chem. Mater. 33 15 2021 5974 5980 10.1021/acs.chemmater.1c01173
163 Yuan B. Wu H. Wang H. Tang B. Xu J.F. Zhang X. A Self-Degradable Supramolecular Photosensitizer with High Photodynamic Therapeutic Efficiency and Improved Safety Angewandte Chemie 133 2 2021 716 720 10.1002/ange.202012477
