
==== Front
iScience
iScience
iScience
2589-0042
Elsevier

S2589-0042(24)01935-7
10.1016/j.isci.2024.110710
110710
Review
The mitochondrial stress signaling tunes immunity from a view of systemic tumor microenvironment and ecosystem
Kuo Cheng-Liang 16
Lin Ying-Chen 16
Lo Yu Kang 1
Lu Yu-Zhi 1
Babuharisankar Ananth Ponneri 17
Lien Hui-Wen 1
Chou Han-Yu 1
Lee Alan Yueh-Luen alanylee@nhri.edu.tw
12345∗
1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
2 Department of Life Sciences, College of Health Sciences & Technology, National Central University, Zhongli, Taoyuan 32001, Taiwan
3 Ph.D. Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing University, Taichung 40402, Taiwan
4 Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
5 Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
∗ Corresponding author alanylee@nhri.edu.tw
6 These authors contributed equally

7 Present address: Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA

13 8 2024
20 9 2024
13 8 2024
27 9 110710© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Summary

Mitochondria play important roles in cell fate, calcium signaling, mitophagy, and the signaling through reactive oxygen species (ROS). Recently, mitochondria are considered as a signaling organelle in the cell and communicate with other organelles to constitute the mitochondrial information processing system (MIPS) that transduce input-to-output biological information. The success in immunotherapy, a concept of systemic therapy, has been proved to be dependent on paracrine interactions within the tumor microenvironment (TME) and distant organs including microbiota and immune components. We will adopt a broader view from the concept of TME to tumor micro- and macroenvironment (TM2E) or tumor-organ ecosystem (TOE). In this review, we will discuss the role of mitochondrial signaling by mitochondrial ROS, calcium flux, metabolites, mtDNA, vesicle transportation, and mitochondria-derived peptide in the TME and TOE, in particular immune regulation and effective cancer immunotherapy.

Graphical abstract

Microenvironment; Immune response; Cancer

Subject areas

Microenvironment
Immune response
Cancer
==== Body
pmcIntroduction

Mitochondria are a critical cellular organelle that performs multiple functions that determine cell survival, including energy production, free radical production, metabolism, calcium signaling, programmed cell death (apoptosis), and autophagy/mitophagy. Mitochondria also are the major source of endogenous reactive oxygen species (ROS) that escape from the electron transport chain during the oxidative phosphorylation process.1 ROS are a group of highly reactive oxygen-containing molecules generated through several mechanisms in cells, including aerobic respiration, metabolic enzymes, and membrane-bound NADPH oxidases.2 Mitochondrial ROS (mtROS) are mainly produced by the electron transport chain (ETC), enzymatic reaction, and uncoupling of oxidative phosphorylation (OXPHOS) during aerobic respiration. For example, superoxide (O2·–) is produced from incomplete electron transfer and leakage of electrons through ETC complexes I, III, and IV1,3 of dysfunctional mitochondria. According to the theory of endosymbiosis,4 mitochondria originated from a phagocytosed bacterium that used oxygen to convert organic molecules to energy by an ancient eukaryotic cell 2.5 billion years ago.5 This arrangement has the mutual benefits to both cell types. The ancient eukaryotic cell acquired a strategy of limiting oxygen, a toxic molecule, which became a driving force for chemical energy within cells. During evolution, this endosymbiotic interaction gradually became further entangled and most bacterial genetic information had almost transferred to the nucleus. The human mitochondrial genome is a 16.5 kb circular double-stranded DNA (mtDNA) with autonomous replicative and gene expression machinery.

Recent evidence involved in the role of mitochondria in immunity provides another possible explanation for endosymbiosis.6 Mitochondria have represented a source of molecules for host defense for a eukaryotic cell. For example, mitochondrial ROS (mtROS) could be used to destroy phagocytosed pathogens or as signals for regulation of gene expression.7 Some mitochondrial components have substantial similarity with bacterial molecules, suggesting that they may function as pathogen recognition receptor (PRR) ligands, such as, the mitochondrial genome (similar to bacterial genomes) that is circular and not associated with histones. Emerging evidence showed that ROS are not only mediators of oxidative stress but also players of immune regulation in tumor progression.8 Paradoxically, ROS act as a double-edged sword in carcinogenesis. First, high level of ROS can damage both nuclear DNA (nDNA) and mtDNA, which cause cell death. Mitochondria have a major role in the control of apoptotic, ferroptotic, and necroptotic forms of regulated cell death, which ultimately involves irreversible mitochondrial permeabilization and hence loss of mitochondrial compartmentalization.9,10 Thus, mitochondria offer a unique platform for damage-associated molecular pattern (DAMP) redistribution, PRRs signaling, and inflammation in the response to cellular stress. In addition, ROS are crucial intermediates of cellular signaling pathways that promote chronic inflammation and tumorigenesis simultaneously.11,12 As a result, mitochondria could master regulators of inflammatory responses, not only as they contain several DAMPs but also as they provide a physical scaffold for the activation of PRRs.13 Many reports indicated that ROS stress enhances mitochondrial DAMP (mtDAMP) production; for example, damaged mtDNA is pivotal for mtDAMPs.14 Due to the bacterial origin of mtDNA, released mtDNA in cytosol can stimulate innate immune systems including TLR9 and cGAS-STING signaling pathways in the mammalian cells.14,15 These suggest the intracellular release of damaged mtDNA stimulates inflammation in response to tumor-induced mitochondrial stress. Therefore, mitochondria are the major organelle in sensing cellular stress and inducing the response and signal transduction for cell survival, which also present or release mtDAMPs that promote inflammation.13

Recently, mitochondria are considered as signaling organelles that dynamically transduce biological information in response to both endogenous and environmental factors. Further, mitochondria are the processor in the cell and communicate with the nucleus and other organelles, which constitute the mitochondrial information processing system (Figure 1). In a three-step process model, Sensing, Integration, and Signaling, mitochondria are able to detect metabolic and environmental inputs and transform these inputs into different states; integrate information through the exchange of information among mitochondria and other organelles and the dynamic-based network interactions produce mitochondrial output signals that tune the functions of other organelles and cell physiology as well as systemically regulate organismal behavior.16 Indeed, there is growing evidence that the mtROS, Ca2+, metabolites, peptides, vesicles, and mtDNA play a "central" role in chronic inflammation that ultimately exacerbates cancer.6,8,17 Moreover, growing findings suggest that eliminating damaged mitochondria by selective autophagy/mitophagy is a powerful tool to control the inflammation in the immune system.18Figure 1 The model of mitochondrial signal transduction in the tumor microenvironment (TME)

Mitochondria in the cytoplasm are positioned at the interface between incoming signals from the outside extracellular environment and the inside compartment of cells. As a mitochondrial information processing system (MIPS), all mitochondria have the ability to perform input sensing, integration, and output signaling that contribute to cellular and organismal adaptation. In this scenario, mitochondria serve as central hubs that integrate input signals to release processed signals into the environment after a complicate information processing. Upon cancer cells stimulated by environmental stresses (blue colored), mitochondria respond and generate integrating signals, such as mitochondrial reactive oxygen species (mtROS), metabolites, mitochondrial DNA (mtDNA), Ca2+, and MDVs, and coordinate the signals under stresses (purple colored). These integration and processing subsequently lead to the release of downstream molecules as input signals (red colored) that then alter the TME. ER, endoplasmic reticulum; EMC, ER-mitochondria contact site; MDVs, mitochondria-derived vesicles; EVs, extracellular vesicles. The scheme was created with BioRender.com.

The strategy to cancer therapy is evolving from a “cancer-cell-centric” perspective to a systematic concept that considers cancer cells as a network of surrounding cells, which is called a tumor microenvironment (TME).8,19 In the past decade, a breakthrough revolutionary cancer treatment, immunotherapy with immune checkpoint inhibitors, has been emerging to control cancer. The response and efficacy to cancer immunotherapy is heavily influenced by their status of TME. For example, hypoxia and elevated ROS status in the TME lead to adaptive mechanism of cell survival, the reinforcement of cell resistance (toward chemotherapy and radiotherapy), angiogenesis that supplies their need for oxygen and nutrients, immunoescape, invasion, and metastasis.8,20 This persistent inflammatory/oxidative environment leads to a vicious cycle that damages healthy adjacent epithelial and stromal cells, ultimately leading to carcinogenesis. In other words, the pre-existing immunity is determining the fate and survival of the patient and the response to immunotherapy. However, in the past few years, many literatures reviewed the observation, indicating that tumors can affect distant sites that may in turn affect primary or secondary tumor development, thus providing evidence to support the view of cancer as a systemic disease.21,22,23,24 For example, the crosstalk within the TME and between organ systems at distant sites and primary tumor contains various growth factors, cytokines, extracellular proteins, and extracellular vehicles (EVs), which affect the development and metastasis of tumor.21 The stress in the TME stimulates the secretion of EVs from primary tumor, which carry DNA and proteins to remodel the microenvironment of distant organ.14,25 Moreover, extensive research has shown to unveil the critical regulatory mechanisms driven by secreting factors from the interaction of tumor and surrounding cells in the TME, from the macroenvironment of distant organ, or from the tumor-host interaction beyond the TME, including nervous, endocrine, microbiota, and immune system.22,23

Therefore, the emerging compelling data indicate that the TME-centric view is too narrow to accurately reflecting the complexities of the systemic networks of tumor. Considering the lack of integrity of the TME cannot represent the effects of the tumor on the whole body environment, the idea of the tumor-organ ecosystem was proposed to describe different engagement microenvironments distant from cancer lesions.22 Since immunotherapy, the newest class of systemic cancer therapies, is to establish a population of highly active and tumor-specific immune cells that can eradicate tumor cells, we will expand a broader view including the concept of tumor microenvironment and tumor macroenvironment elements into the scope of tumor-organ ecosystem (TOE) to discuss the role of mitochondrial stress in cancer immunotherapy, in particular some systemic immune components. We will interpret the latest compelling evidence of how tumor cells process the mitochondrial ROS regulation to interact with the components in the TME and TOE. Here, we will interpret how tumor cells process mtROS, Ca2+, metabolites, peptides, and mtDNA/EV to interact the components in the TME and TOE by different mechanisms and aspects (Figure 2): (1) mtROS balance in inflammation and cancer immunoescape in the TME; (2) calcium flux in mitochondrial signaling in the TME; (3) mitochondrial metabolism and metabolites of cancer cells and microbiota in the cancer and immune cells in the TME and TOE; (4) mtROS-induced mtDNA leakage and EV in the immunoescape in the TME and TOE; (5) the translational significance of mitochondrial modulation in the cancer immunotherapy.Figure 2 Mitochondria synthesize and release signals evolved to alter cellular functions in the tumor microenvironment (TME)

Schematic illustration of major mitochondrial pathways modulating cancer malignancy under stressed TME.

(A) Mitochondria are key hubs for ROS generation. Under stresses, the mitochondrial chaperone protein Lon coordinates with the ETC complex I subunit, NDUFS8, and PYCR1, leading to the production of mtROS. This phenomenon triggers pathways related to anti-apoptosis, angiogenesis, epithelial-mesenchymal transition (EMT)/metastasis, and immunosuppression in cancer cells.

(B) Oncometabolites may be secreted into the TME and potentially exert negative effects on the peripheral immune system. Lactate, a glycolysis product enriched under the Warburg effect, has been found to boost mitochondrial activity via oxidative phosphorylation (OXPHOS). The shift suggests that mitochondrial metabolism has some defects in TCA cycle and is taken over by glycolysis in cancer metabolic pathways.

(C) The generation of mtROS impacts mtDNA causing fragments that are released into the cytosol and induce cellular PD-L1 expression. This process further drives immunosuppressive pathways associated with tumorigenesis. mtPQC, mitochondrial protein quality control; PYCR1, pyrroline-5-carboxylate reductase 1; NDUFS8, NADH-dehydrogenase ubiquinone iron-sulfur protein 8; NF-κB, nuclear factor kappa-light-chain enhancer of activated B cells; STAT, signal transducer and activator of transcription; HIF-1ɑ, hypoxia-induced factor 1 alpha; AMPK, adenosine-monophosphate-activated protein kinase; NADPH, nicotinamide adenine dinucleotide phosphate; STING, stimulator of interferon gene; TBK, TANK-binding kinase; IFN-γ, interferon gamma; PD-L1, programmed cell death receptor ligand 1; TLR9, Toll-like receptor 9; ATP, adenosine triphosphate; PI3K, phosphoinositide 3-kinase; IL-1β, interleukin-1β; IL-6, interleukin-6; M2 TAMs, M2 tumor-associated macrophages; SUCNR1, succinate receptor 1; PDH, pyruvate dehydrogenase; TCA cycle, tricarboxylic acid cycle; GM-CSF, granulocyte-macrophage colony-stimulating factor; PBMCs, peripheral blood mononuclear cells. The scheme was created with BioRender.com.

The mitochondrial ROS stress in cancer modulates the tumor microenvironment

Recent basic and clinical study has proved that cancer progression is driven not only by genetic alterations but also by paracrine interactions within the TME including the immune system. The major stress phenotypes of the TME include hypoxia and continuous oxidative stress, which also are the reason of chronic inflammation. Mitochondria are known as a major source of ROS for communication or host defense for a eukaryotic cell. Accumulating evidence showed that ROS are not only mediators of oxidative stress but also players of immune regulation in tumor progression. The understanding for the ROS regulation, communication, and interaction within the TME is highly crucial to the efficacy of cancer immunotherapy (Figure 2A). In addition, ROS level can be controlled by their localization within the cell, i.e., ROS protection via compartmentalization including the control of mitochondria turnover and localization.26 For example, mtROS can be eliminated and controlled by mitophagy that removes damaged ROS-producing mitochondria8,27 (Figure 3).Figure 3 The scheme of the interaction and communication between mitochondria and ER regulate mitophagy and cell survival under stresses

Mitochondrial machinery that crosstalks with organelles boosts cancer malignancies under stress condition in the TME. Upon ROS and hypoxia condition, mitochondrial chaperone Lon promotes FUNDC1-ULK1-mediated mitophagy at the EMC/MAM site via forming the complex, which is dependent on the binding with mitochondrial Na+/Ca2+ exchanger (NCLX). Cisplatin treatment and ROS cause mtDNA damages and further induce Lon protein expression that is a mtDNA-binding protein. Mitochondrial Lon activates NCLX to release mitochondrial calcium (Ca2+) to the cytosol. Cytosolic Ca2+ thereby stimulates the STAT3 signal pathway. Activated STAT3 translocates to nucleus to activate IL-6 and Bcl-2 expression that increases the survival of cancer cells leading to cisplatin resistance. EMC/MAM, endoplasmic reticulum-mitochondria contact site/mitochondria-associated membrane; Ca2+, calcium ion; ULK1, Unc-51-like kinase 1; LC3B, microtubule-associated proteins 1A/1B light chain 3B; MCU, mitochondrial calcium uniporter; NCLX, mitochondrial sodium calcium exchanger; FUNDC1, FUN14 domain containing 1; DRP1, dynamin-related protein 1; VDAC, voltage dependent anion channel 1; STIM1, stromal interaction molecule 1; STAT3, signal transducer and activator of transcription 3; Bcl-2, B-cell lymphoma 2; IL-6, interleukin-6. The scheme was created with BioRender.com.

The impact of mitochondrial ROS from cancer on immune response in the tumor microenvironment

Continuous ROS generation from mitochondria under aggravated oxidative or hypoxic stress induces the chronic inflammation that is one of the major features in the TME; the mechanisms of how oxidative stress modulates chronic-inflammation-induced carcinogenesis from the TME point of view have been described in many reviews.8,13,26 However, the understanding for the ROS regulation, communication, and interaction within the TME is highly crucial to the efficacy of cancer immunotherapy. The key issue of cancer immunotherapy is trying to keep the TME from the “cold” to the "hot" state. ROS are used by cancer cells and immunosuppressive immune cells to create immune tolerance to tumors (Figure 2A). It is widely recognized that ROS promotes pro-inflammatory cytokines production, for example, ROS-induced signaling triggers hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), Janus kinase-signal transducer and activator of transcription (JAK/STAT), stimulator of interferon genes (STING), and mitogen-activated protein kinase (MAPK) pathways.8 In cancer cells, elevated ROS have been shown to contribute to metastasis and angiogenesis through the secretion of inflammatory cytokines, the stabilization of HIF, and activation of AMPK signaling networks to enhance NADPH production.28,29 Both in cancer cells and macrophages, mitochondrial function is an important regulator and controller for mtROS generation.8,14,30 The normal function of mitochondria is dependent on the protein quality control (mtPQC) that is regulated by the protease and chaperone system.31 Mitochondrial Lon (LonP1) is a multi-function protease/chaperone as well as a stress protein in the matrix, which is induced by multiple stresses, such as starvation, endoplasmic reticulum (ER), hypoxia, and oxidative stress.32 The upregulation of mitochondrial Lon increases ROS generation that promotes cell proliferation and transformation via interacting with the complex I of ETC and pyrroline-5-carboxylate reductase 1 (PYCR1).30,33 Moreover, the mitochondrial-Lon-induced mtROS-dependent NF-κB activation stimulates inflammatory cytokines release from cancer cells to exacerbate immune suppression status in the TME.30 Among ROS-induced inflammatory signaling, NF-κB is constitutively activated in many different types of cancer and promotes a variety of inflammatory factors.34 Another well-known signaling that responds to ROS in promoting tumorigenesis is MAPK cascades. ROS-induced MAPK activation can also regulate NF-κB signaling to promote inflammatory factors secretion, such as interleukin- 1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α).34,35 For example, Kuo et al. showed that NF-κB and MAPK promote inflammatory cytokines expression, including IL-6 and vascular endothelial growth factor (VEGF) that are regulated by Lon-induced ROS.30 On the other hand, ROS exert a significant impact on the expression of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in the TME (Figure 2A). Through binding with PD-1, an inhibitory immune checkpoint receptor on the surface of tumor cells, PD-L1 (B7-H1), attenuates the effector function in dendritic cells (DCs) and macrophages.

The balance of mitochondrial ROS stress by dynamics and mitophagy modulates immune response in the tumor microenvironment

Since ROS are a critical player of immune regulation in tumor progression and its generation is closely related to morphological features and function of mitochondria,8 mitochondria dynamics and mitophagy will protect cell from oxidative stress to enhance cell survival and immunoescape. Indeed, redox imbalance upon mitochondrial morphological alteration will contribute to promote chronic inflammation, metastasis, and chemoresistance development in multiple cancer models.36 In addition to cancer cells, the immune cell differentiation, activation, and cytokine infiltration were also controlled by the mitochondrial-dynamics-induced ROS.37,38 The fusion and fission machinery of mitochondria was organized and orchestrated by dynamin-related protein 1 (Drp1), dynamin family GTPases, optic atrophy protein 1 (Opa1) on the inner membrane, and mitofusin (Mfn) 1 and 2 on the outer membrane with support from mitochondrial fission factor (Mff), Fis1, and Mid49-51. mtROS generation during stress stimuli causes activation and recruitment of Drp1 to mitochondria to initiate fission and suppress fusion through Mfn1. Fission through Drp1 S616 phosphorylation triggers mtROS production that activates NF-κB-dependent cytokine production. The Drp1 activation in immunotherapy treatment enhances the antitumor immunity.39 Mitochondrial Drp1 plays an integral role in T cell death and depletion of exhausted T cells by controlling abnormal ROS levels alongside with damaged mitochondria. Activation of T cell requires immune synapse (IS) formation where the redistribution of mitochondria and mitochondrial positioning to IS was regulated by Drp1.40 On the other hand, T cells also require mitochondrial fusion to increase the OXPHOS function that is the major contributor for mtROS generation and T cell exhaustion that is the huge obstacle to the cancer immunotherapy for solid tumors.41 Besides T cells, mitochondrial dynamic distribution is important for the DCs and macrophages. Mitochondrial fusion proteins Mfn2 and Opa-1 were upregulated in GM-CSF-stimulated immature DCs from bone-marrow-derived progenitor cells, and IL-12 secretion was increased in bone-marrow-derived macrophages (BMDMs) and bone-marrow-derived DCs (BMDCs) from MIGA2MKO upon loss of Mfn/Opa-1. The diverse form of human DC subsets regulates the mitochondrial dynamics based on Drp1 and Mfn. Myeloid DCs (mDCs) have higher Drp1 expression, whereas plasmacytoid DCs (pDCs) largely depend on the Mfn function in DCs.42 Collectively, these reports highlight the significance of mitochondrial dynamics interplay with mtROS is essential for maintaining cellular homeostasis or triggering cell-survival/cell-death-mediated immune response.

Mitophagy, a conserved mitochondrial quality control response, eliminates the damaged mitochondria to maintain the healthy mitochondrial population, mass, and homeostasis. Thus, the maintenance of mtROS balance depends on the mitophagy upon hypoxia or ROS stress condition, which facilitates hypoxia-induced drug resistance and immunotherapy.43,44 The level of mitophagy occurrence decides the cancer progression property. Mitophagy activation upon hypoxia and oxidative stress has a serious role in response to inflammatory response and immune microenvironment, which reflects autophagy/mitophagy inhibitors may have a synergistic response with chemo-drugs or immune checkpoint therapy to promote anti-tumor function. Recently, lung cancer stem-like cells responsible for chemoresistance and recurrence promote hyperactivation of mitophagy that leads to mtDNA accumulation in lysosomes, which triggers mitochondrial metabolic stress through TLR9-Notch1-AMPK axis.45 The elimination of damaged mitochondria by mitophagy resembles the stress adaptation, thereby keeping the immune system in check.46 Innate immune response is the front-line defense by host against the microbial invasion, and mitochondria can be considered as the pivotal hub for the stimulation of innate immune system. Depletion of autophagy proteins LC3B and Beclin1 causes the accumulation of damaged mitochondria and the release of mtDNA to cytosol that increases the secretion of IL-1β and IL-18 in macrophages.47 In addition, the NF-κB restricts the inflammasome activation that releases mtDNA and mtROS by activating parkin-p62-dependent mitophagy to promote homeostasis maintenance.48 The role of mitophagy in innate immune response was interlinked with metabolic signaling and certainly proves the significance of mitophagy inhibition as serious therapeutic target in cancer immunotherapy. Collectively, the regulatory components of mitophagy are important for the innate immune response preventing mitochondrial integrity loss; on the other hand, they are important for the survival and immune suppression response in cancer progression.

The stress-induced calcium flux and the mitochondrial signaling modulates the tumor microenvironment

During hypoxia and ROS stress, mitochondria are the nexus of cell death and survival mechanisms for sensing and signal processing response to the stresses. One of the most studied examples of mitochondrial sensing and signal processing is calcium (Ca2+). Mitochondrial Ca2+ uptake from the cytoplasm and ER triggers rapid changes in mitochondrial physiology. Under hypoxia or ROS stress, mitochondrial signaling is involved in the inter-organellar crosstalk between the ER and mitochondria.

The dynamic association between ER and mitochondria is necessary for the physiological function of mitochondria determining mitochondrial fission/fusion, mitophagy, lipid drifting, and Ca2+ shuttling. In this section, the mechanism of how mitochondrial signaling facilitates the demand changes in increased mtROS or altered Ca2+ flux to induce morphological changes in mitochondria upon the physiological stress in cancer and immune cells is discussed (Figure 3). It will govern the function of mitochondrial signal transduction upon stress-induced Ca2+ flux and mitophagy, providing a future combination of cancer immunotherapy for patients.

The stress-induced mitochondrial calcium flux in the regulation of immune response in the tumor microenvironment

The calcium flux between mitochondria and ER modulates mitochondrial functions through regulation of OXPHOS, ROS signaling events, and cell death control. Regarding mitochondrial Ca2+-mediated cell death, mitochondria are known as the source of multiple cellular DAMPs, and mitochondrial DAMPs (mtDAMPs) are released upon mitochondrial stress or damage that have pro-inflammatory properties. These mtDAMPs include mtROS, mtDNA, cardiolipin, N-formyl peptides (NFPs), and some metabolites, such as ATP and succinate.49 The most-studied DAMP release is the Ca2+-dependent protein calreticulin (CRT),50 which is recognized by DCs to induce immunogenic cell death (ICD). Moreover, CRT exposure on the surface of cancer cells and ATP secretion by Ca2+ ionophore A23187 trigger ICD response by promoting tumor antigen presentation and tumour-specific CTL responses.51 The calcium influx into the mitochondria generates ROS and release of damaged mtDNA, contributing to the amplification of NLRP3 (nucleotide-binding domain, leucine-rich repeat-containing family, pyrin-domain-containing 3) inflammasome activation.52 From this viewpoint, calcium signaling is undoubtedly the central mediator of many biological processes particularly in the context of an immune regulation. One of the important calcium transfer machinery in mitochondria is mitochondrial calcium uptake protein 1 (MICU1); the discovery of MICU1 leads to the identification of MCU (mitochondrial calcium uniporter) that allows the calcium influx directly to the mitochondrial matrix.53 The significance of MCU activation does not only regulate mitochondrial calcium but also associate with the negative regulation of cytosol and ER calcium dynamics. On the other hand, the mitochondrial Ca2+ efflux is regulated by Na+-Ca2+ exchanger (NCLX) and putative mitochondrial H+-Ca2+ exchanger Letm1.54,55 A recent study showed that the resistance mechanism by mitochondrial chaperone interacting with NCLX inhibits excess mitochondrial calcium influx induced by cisplatin to trigger cell death.44 Most importantly, MCU recently has been involved to play role in innate immune response. MCU inhibiting ESCRT (endosomal sorting complex required for transport)-III complex-mediated phagolysosomal membrane repair is uniquely required for maximal activation of the NLRP3 inflammasome via a phagocytosis.56 In addition, Ca2+-dependent signaling is critical in the functioning of tumor-associated macrophages (TAMs), which could both sustain tumor growth and exert anti-tumor effects under certain conditions.57 The response of mitochondrial calcium channels in T cell was still unclear, and conducting more scientific evaluations is necessary to define its significance. However, plasma membrane voltage-dependent Ca(2+) channel Ca(V)1.4 is essential for intracellular Ca(2+) homeostasis to control naive T cell homeostasis and antigen-driven T cell immune responses.58 To support the cytosolic calcium importance in immune cells, transient receptor potential melastatin 5 channel (TRPM5), one of the calcium-activated monovalent cation channels (CAMs), negatively regulates the cytosolic calcium regulation, leading to LPS stimulation B cell proliferation and cytokine infiltration.59 Although immunotherapy is a promising field and Ca2+ signaling could augment treatment efficacy, the ubiquity of Ca2+ in normal metabolism and cellular function makes greater understanding of specific mechanisms in Ca2+ signaling necessary before such dreams become attainable.

The stress-induced ER-mitochondria communication modulates calcium flux in the immune response in the tumor microenvironment

In the model of mitochondrial information processing system, mitochondria are the signal processor in the cell and communicate and integrate with the nucleus and other organelles, for example, ER. The ER-mitochondria contact (EMC) sites, also called mitochondria-associated membranes (MAMs), have been demonstrated to be involved in mitophagy, lipid metabolism, and Ca2+ transport, indicating the fact that organelle communication is important for the cellular signaling16 (Figure 3). The dynamic association between ER and mitochondria is necessary for the multiple function of mitochondria determining the cellular fate and death, including mitochondrial fission/fusion, mitophagy, lipid drifting, and Ca2+ shuttling.60 Most importantly, mitochondrial chaperone is involved in the inter-organellar crosstalk between the ER and mitochondria at the EMC. Upon hypoxia stress, mitophagy initiation is elucidated by the translocation of mitochondrial stress protein from the matrix to the EMC region, which provides the signaling mechanism from inside mitochondria to outside contacts. Intriguingly, the mechanism is dependent on Ca2+ flux through the binding with mitochondrial Na+/Ca2+ exchanger (NCLX)44 at the EMC site. The control of cytosolic Ca2+ oscillations by NCLX was associated with many pathological conditions including cancer and immune cells. The sustained intracellular Ca2+ levels in cancer cells can activate the AMPK-ULK1 phosphorylation and FUNDC1 signaling during mitophagy,61 highlighting the significance of calcium-mitophagy coordination in regulating the cell proliferation during various stress conditions. Recent publications have suggested that calcium signaling could be used to improve the efficiency of immunotherapy approaches by enhancing antigen presentation and in the adaptive immune response. The study by Yoast et al. demonstrated that MCU depletion in immune cells allows enhanced SOCE (store-operated Ca2+ entry) cytosolic Ca2+ in response to passive store depletion, and ER Ca2+ refilling increases the activity of the nuclear factor for activated T cells (NFAT) transcription factors in T cell and B lymphocyte proliferation in response to receptor stimulation.62 These findings define an important function of the ER-mitochondria communication that integrates calcium-mitophagy coordination, and it governs the function of mitochondrial signal transduction upon hypoxia-induced mitophagy, providing a future choice of combination cancer immunotherapy for patients. In the future, the mechanism of how mitochondrial signaling facilitates the demand changes in increased mtROS, altered Ca2+ flux, or lipid biosynthesis to induce morphological changes at the EMC sites is worth further investigating upon the physiological stress demands from cancer and immune cells.

The effect of mitochondria- and microbiota-associated metabolites on cancer and immune cells in the tumor microenvironment and the tumor-organ ecosystem

Tumor cells have developed adaptive mechanism to survive under various extreme conditions of the TME by interacting with these neighbor stromal cells through signaling molecules, cytokines, and metabolites.63 The resources in the TME are limited, so that further triggers metabolic competition between cells among the TME due to quick expansion of these tumor cells. For example, most studies have indicated that glucose deprivation from cancer cells may create competitive conditions in the TME due to simultaneous high consumption by cancer cells and activated immune cells.64 The mitochondria-involved metabolism includes OXPHOS, the tricarboxylic acid (TCA) cycle, mitochondrial membrane potential, and the release of mtROS and mtDNA. The mitochondrial metabolism in cancer cells plays a pivotal role through no matter “inside-out” or “outside-in” bi-direction communication with the components in the TME, including immune system.65 Cancer cells also lower pH value via releasing of lactic acid, and this kind of cell-extrinsic metabolism pathways stand as a hot point of metabolic reprogramming research and development of therapeutic strategy. Therefore, how cancer cells initiate, build up, and eventually complete the immunosuppressive TME via mitochondrial activities is another focused issue. Moreover, metabolites that accumulate upon dysregulation of metabolism among tumor tissues also contribute to diminish immunity against cancer cells, which is so-called oncometabolites.66 In addition to oncometabolites, mitochondria in cancer cells are powerful in altering the TME by releasing mtDAMPs. Cancer progression and metastasis is driven by paracrine interactions between the TME and distant organs including microbiota, which is so-called tumor-organ ecosystem (TOE).21,67 In this section, we summarize and discuss evidence on how mitochondria in cancer cells participate in the TIME establishment and subsequently influence immune cells via mitochondria in this challenging environment (Figure 2B).

The effect of mitochondria-associated metabolites from cancer on immunity

Here, we categorized the metabolic reprogramming mechanisms that are directly released from cancer cells into three groups: (1) metabolic competition and deprivation between cancer cells and immune cells, (2) direct alteration or inhibition of immune activities via oncometabolites triggering, (3) inhibition of immune cells led by over-exposure under tumor-derived mtDAMPs. Thus, the intrinsic mitochondrial metabolic activities of cancer cell deteriorate the TME and further provide oncometabolites to sustain malignant characteristics. Based on the type of stress and disease condition, mitochondrial events pose a challenging environment for the activation or suppression of the immune system that is endorsing survival or death events, termed as “immunometabolism.” Oxidative and hypoxic stress are key representatives of cancer, causing alterations in the biological process responsible for mitochondrial activity and metabolism. This explains the importance of mitochondrial-mediated metabolic pathways having direct or indirect effects on triggering immune cell growth and function. Followed by promoting cancer cells to progress and proliferate, oncometabolites are initiated by abnormal accumulation of metabolites that are due to aberrant physiology of extracellular environments. For instance, TAMs are reported to be affected by succinate, a key intermediate in the Krebs cycle, to perform anti-inflammatory markers Arg-1, Mgl1/2, and Fizz-1,49 and it showed pro-angiogenic ability via elevation of IL-1β that indirectly promotes inflammation-induced angiogenesis. Tumor anabolism is supplied by cell-intrinsic mitochondrial metabolic activities by providing some key molecules and further providing oncometabolites to sustain malignant characteristics.

The metabolic reprogramming in T cells in the tumor microenvironment

In the TME, metabolic reprogramming from OXPHOS to aerobic glycolysis (termed the "Warburg effect") in cancer leads to a progressive function loss of T lymphocyte. In the state of "immunosurveillance," the major metabolic pathway of T cells is glycolysis, which uses the glutamine decomposition to drive anabolic growth program and at the same time closes the pathway of fatty acid oxidation.68 However, hypoxic tumor cores enhance glucose uptake and glycolysis in cancer cells exacerbating glucose starvation and accumulation of lactate in the TME. Accumulation of lactate increases acidity in the TME and affects immune pathways, impairs antitumor T cell responses, and hinders T lymphocyte function, which is through multiple mechanisms—inhibition of energy acquirement, disruption of TCR signaling, upregulation of PD-1, and production of immunosuppressive cytokines. In addition, the antigenic stimulation and function of T cell are constantly inhibited by mitochondrial dysfunction and metabolic stress under hypoxic TME. Major mitochondrial dysfunctions include defects in the OXPHOS pathway, depolarization, reduced mass, and activity and ultimately result in inefficient and functionally exhausted T cell metabolism.69

The metabolic challenges affect the metabolic fitness and anti-tumor activity in tumor-infiltrating T lymphocytes (TILs). For example, the continuous involvement of T cell in antigen presentation leads to T cell exhaustion. Loss of PPAR-gamma coactivator 1α (PGC1α) in tumor infiltrating T cells causes decreased mitochondrial biogenesis, and thereby OXPHOS metabolism and ATP production were compromised to enhance immune suppression.70 On the other hand, the mitophagy induction upon depolarized mitochondria accumulation after nicontinamide riboside treatment is important for the metabolic fitness of T cells by downregulating mtROS and Drp-1-mediated fission.71 In addition, inflammatory cytokines have more effects on mitochondrial dynamics that regulates the differentiation of T cells. These suggest that mitochondrial dynamics and metabolism is important for the differentiation and function of effector T cells through cristae remodeling and metabolic reprogramming.

The mitochondria-associated metabolites in dendritic cell in the tumor microenvironment

In recent years, the metabolic needs of DCs have been gradually discovered, and subsets and specific metabolic phenotypes in DCs are strongly linked to their functions, showing promising prospects for cancer treatment in the future. DCs can be classified dichotomously into two types under physiological conditions: immunogenic DCs and regulatory DCs (regDCs). Immunogenic DCs are activated in response to pathogenic molecules, bridging innate and adaptive immunity, whereas regDCs suppress excessive immune responses to prevent autoimmune dysregulation. Accumulating evidences suggests that the metabolic transformation is a decisive factor in determining the function of these two types of DCs.72 Different from metabolic form of DCs immune activation, tolerogenic or regulatory DCs show more competency in OXPHOS and FAO, and this transformation is speculated to support high consumption of energy that is associated with protein degradation and exert inhibitory effect. Furthermore, mitochondrial activities and ROS level were found increased in tolerogenic DCs.73 Interestingly, it is conceivable that this DC metabolic reprogramming machinery is still conserved in the TME. The glycolytic activities of DCs were downregulated by inhibiting hexokinase (HK) and phosphofructokinase (PFK-1) followed by decreased extracellular acidification rate (ECAR) and increased oxygen consumption rate (OCR), which indicated OXPHOS of DCs was meanwhile promoted. Consistently, decreased ECAR and upregulation of OCR are observed in this dysregulated DC program. In these DCs, mitochondrial mass and mitochondrial membrane potential were increased for processing excessive extracellular FAs sources as previously described.74 These two studies respectively used etomoxir (ETO) and GW6471—the former is mitochondrial fatty acid transporter inhibitor and the latter is PPAR-α inhibitor—to rescue immune capabilities of DCs and proclaimed better outcome when combined with immune checkpoint blockade (ICB) therapies.75,76 These evidence surrounded that metabolic transformation toward FAO, and intensified mitochondrial competencies are a key tipping point for DCs to express inhibitory effect in the TME. Taken together, though metabolic transformation in DCs is conserved across non-malignant to malignant diseases, more pre-clinical evidence toward DCs need to be uncovered to fully speculate practical targets of cancer immunotherapy.

The effect of microbiota metabolites on the tumor microenvironment and the tumor-organ ecosystem

Mitochondria in cancer cells are powerful in altering the TME by releasing metabolites. In addition, since mitochondria are believed to be evolved from an endosymbiotic organism, we will expand the view and discuss the role from mitochondrial to microbiota signaling in the interaction with the components within the TME and TOE. The gut microbiota is a diverse community of microbes living in the gastrointestinal tract of animals, which is well studied in many aspects of diseases. Dysfunction between the gut microbiota and the host is associated with a variety of diseases, including neurological diseases, metabolic defects, and cancers.77 Microbial metabolites modulate cancer progression by regulating and remodeling the level of cytokines and the function of immune cells in the TME. Microbiota-derived metabolites are significant and important modulators of the TME, triggering the release of substances from immune cells and tumors.78 Herein, we will delve into the impact of microbiota-derived metabolites on cancer cells and immune cells, exploring their role in promoting drug resistance, which represents a significant obstacle in cancer treatment, based on the latest literature findings (Figure 4).Figure 4 The scheme of mitochondrial stress signaling regulates inflammation and immunity to promote tumorigenesis from a view of the tumor microenvironment (TME) to the tumor-organ ecosystem (TOE)

Mitochondria are the major cellular source of ROS generation due to the metabolic process. Chaperone Lon binds with NDFUS8 in the complex I of electron transport chain and with PYCR1 reductase to upregulate mitochondrial ROS (mtROS) generation that promotes cell proliferation and inflammation. mtROS cause the oxidative damage on mtDNA and induce IFN signaling that upregulates PD-L1 expression to inhibit T cell activation. Under ROS stress, cancer cells produce NF-κB-dependent inflammatory cytokines, TGFβ, VEGF-A, IL-6, and IL-10, to cause the immunosuppressive state of macrophages, dendritic cells (DC), and T cells (Treg). In addition, Lon upregulation by ROS and hypoxia induces the secretion of extracellular vehicles (EVs) that carry mtDNA and PD-L1. Therefore, mtROS cause an immunosuppressive TME to promote immunoescape, survival, and EMT/metastasis of cancer cells. Recently, the emerging data indicated that the TME view is too narrow to accurately reflect the complexities of the systemic networks in tumor. Since we consider cancer as a systemic disease, cancer progression and metastasis is driven by paracrine interactions within the TME and by distant organs including microbiota in the tumor-organ ecosystem (TOE).

Recent reports have unveiled a rapidly expanding array of microbial metabolites that demonstrate the potential to directly or indirectly enhance tumor progression. These findings typically stem from understanding the specific mechanisms underlying various cancer types, bacterial strains, or immune compositions. Studies have delved into novel microbiota-associated metabolites that directly promote tumor advancement or contribute to a newly identified cascade within the microbiota-cancer cell axis. For instance, a latest research associated with Fusobacterium nucleatum (Fn), recognized as a major strain of protumorigenic bacteria in the microbiota,79 had secreted formate to promote colorectal cancer cell (CRC) stemness and glutamine metabolism pathway. While a parallel study based on CRC patients showed, Fn in CRC further promoted cancer progression via affecting distribution of intestinal microbiota; the study discovered increased population of Lactobacillus that secreted lactic acid, whereas propionic-acid-producing Bacteroides populations were decreased in the CRC tissues,80 emphasizing the role of metabolites between microbiota and tumorigenesis.

In addition to examining the direct correlation between microbiota-derived metabolites and cancer progression, the significance of the interaction between the metabolites and the immune system in establishing the malignant TME is underscored. Herein, we organized the latest findings to indicate that microbiota-derived metabolites are capable of affecting the TME and provide insights for subsequent researchers to develop novel therapies targeting microbiota metabolites that suppress anti-cancer immunity. The intricate interplay between the microbiota and the host immune system commences from the birth, as the microbial community plays a pivotal role in initiating immune development and subsequently orchestrating microbiota components.81 Beyond those known factors that have already been published in several review articles, including short-chain fatty acid (SCFA), polyamine metabolites, bile acid (BA), taurolithocholic acid (TLCA), and LCA,82,83 these factors have been identified as capable of impairing the immune system’s ability, thereby enhancing the pro-tumorigenic potential. Previous study has found that Fn-secreted formate in CRC not only facilitates cancer progression via the AhR pathway but also induces the proliferation of IL-17+CD4+RORγT+ T cells (Th17 cells) in the mesenteric lymph nodes (MLNs), indicating a proinflammatory profile of the tumor immune microenvironment that favored CRC development.84 Additionally, tumor-associated macrophages (TAMs) exhibited increased expression of pro-tumor genes, including Arg1, Ido1, and Il10. As a result, intratumoral CD8+ T cell activity was dampened, accompanied by a reduction in the secretion of granzyme B and interferon gamma (IFN-γ). These findings collectively suggest a heightened malignancy of PDAC due to the interplay between bacterial metabolism and immune cells. Another study of breast cancer had echoed that gut Lactobacillus may act as a negative role in tuning TME.85 This study had identified lactic acid as main trigger of polarizing TAMs into M2 type and impairing activity of T cell populations in the TME. Moreover, a study conducted on oral squamous cell carcinoma (OSCC) yielded comparable findings. Specifically, this was mediated by the accumulation of GLUT1, a process triggered by Fn-induced GalNAc-Autophagy-TBC1D5 signaling cascades. Fn-OSCCs-expressed lactate was thus polarized TAMs to M2 type and depraved anti-tumor immunity, eventually promoting a breeding ground for tumor progression.86

The interplay among gut microbiota, immune cells, and malignant tumor development presents a crucial concept of "interaction" within the TOE. Understanding the interplay and these microbiota-metabolites relationships provides more aspects of therapeutic strategies against cancer. Consequently, we have revisited the latest evidences concerning microbiota-derived metabolites emerge as significant players and potentially contribute to alter immune cells and tumor progression. For example, a study focusing on lactic acids identified a correlation between poor prognosis and tumor-resident L-lactate-producing Lactobacillus iners in cancer patients. Interestingly, a significant association was observed between L-lactate-producing bacteria in other body organs and the survival rate of various organ types of cancer, such as colorectal, lung, head and neck, and skin.87 Other research suggests that the metabolites can disseminate to other organs through the bloodstream or other propagation pathways, thereby providing a conducive environment for neoplastic development.88 Tryptophan is an essential amino acid that is metabolized by gut microbes into a potent immune-modulatory product that binds to AhR. Tryptophan metabolites inhibit pro-inflammation by acting on AhR in T cells or astrocytes. In addition, Bacillus-derived poly-gamma-glutamic acid (gamma-PGA) stimulates DCs to favor the polarization of naive CD4+ T cells toward Th1 rather than Th2.89 These studies underscore the intimate interaction within the trans-kingdom network between tissues and bacteria. Similar to mitochondria and their endosymbiotic relevance, microbiota-derived metabolites represent another critical aspect that significantly influences the TME. Further understanding of the metabolites of microbiome and the interactions with the TME and TOE is needed to understand the impact of microbiome dysfunction and the possible use of the microbiome in cancer prevention.

Mitochondrial DNA release and damage-associated molecular patterns stimulate the immune response

Mutation and depletion of mtDNA-induced instability are frequently observed in all types of human tumors, denoting that mutations may contribute to tumorigenesis, metastasis, recurrence, or drug response. Mutations in the D-loop affect coding sequences and mtDNA transcription and replication, potentially affecting the OXPHOS system.90 Sustained oxidative damage to mtDNA leads to downstream dysfunction of OXPHOS and further induces a vicious cycle of ROS production that causes mtDNA damage in tumor cells. In addition, mild (but not severe) mutations in mtDNA affect various components of the ETC, as they promote ROS production in several types of human tumor.91

Numerous evidences have shown that mitochondria are not only responsible for metabolic regulation and signal transduction but also play a central role in the innate immune response.92 The mitochondrial alarmins or mtDAMPs are endogenous danger molecules or altered metabolism products of dead or stressed cells, which are served as endogenous alarm signals to the innate immune system. Emerging evidences have shown that mtDNA, as a part of mtDAMPs, induces an immune response and inflammation in immune cells (Figure 2C). Defective mitophagy or escape from mitophagy pathway causes mtDNA releasing to cytosol, which acts as a mtDAMP to regulate inflammatory responses by triggering interferon genes, TLR9, and the inflammasome.93 Accumulation of mtDNA mutations or deletion, excess mtROS production, altered mitochondrial dynamics, and loss of mitochondrial membrane potential exacerbate mitochondrial dysfunction and inflammasome activation. The presence of bacteria-like hypomethylated CpG motifs in mtDNA have also been pointed out as DAMP that can be recognized by the innate immune system. Previous study suggested that damaged mitochondria, N-formyl peptides, and mtDNA all can act as DAMPs that trigger the innate immune system.94 Studies have also pointed out that plasma-derived exosomes carry mtDNA and trigger an inflammatory response through the TLR9-NF-κB pathway, and the inflammatory effect is closely related to exosomal-mtDNA copy number.14,95 Thus, liquid biopsies based on mtDNA or exosomes could serve as potential biomarkers of physiological stress or immune system response, providing a non-invasive tool to monitor human health and disease.96 Recent studies suggest that mtROS also drives mtDNA damage and mitochondrial antiviral-signaling protein (MAVS) oligomerization, leading to the production of type I interferon independent of RLRs, suggesting that MAVS may act as a key sensor of mtROS that promotes host defense and inflammation.97 MAVS protein localizes on the mitochondrial outer membrane, peroxisomes, and mitochondria-associated endoplasmic reticulum membrane (MAM).98 In addition, the recognition of mtDNA or DAMPs that are produced or released by damaged and dying cells induces sterile inflammation, which is necessary for tissue repair and regeneration but also contributes to the progression of inflammatory diseases such as metabolic disorders and cancers.

Somatic mutations in cancer cells can generate tumor-specific neoepitopes and represent the antigenic determinants of neoantigens, which are recognized by T cells in the host and can elicit immune response to cancer.99 It is well known that mtDNA has a higher basal mutation rate compared with the nuclear genome, however, less known about the mtDNA-encoded antigens recognized by tumor-infiltrating cytotoxic T cells.100 Previous study suggested that mutations of cytochrome b mRNA are leaked out of the mitochondria and then produce translated neopeptides in melanoma cells for stimulating specific CD4+ T cells. The study showed the first novel evidence that mutated peptides encoded in mitochondrial genome may induce specific immune response. Peptide vaccines generated from mutations of COX1 in mitochondria of RENCA cells can elicit cytotoxic T cell responses in vivo, showing altered mitochondrial proteins or tumor-associated mitochondrial antigen (TAMA) to be potentially immunogenic, suggesting that they may be a potential target for cancer immunotherapy.101 In summary, neoantigens may be a promising biomarker in cancer immunotherapy; this emerging field requires more research to understand the molecular mechanisms linking mitochondrial localization of mutated mtDNA to T cell immunogenicity in patients with different types of cancer.

Mitochondrial-stress-induced secretion that contributes to immunoescape

Mitochondria influence the extracellular vesicle release for immune regulation

Microvesicles and exosomes are the two major classes of extracellular vesicles (EVs), whereas exosomes are the derivative of multivesicular bodies (MVBs) that fuse with plasma membrane and protrudes out to reach the neighbor cells. When cancer cells are subjected to hypoxia, pH changes, nutrient shortages, impaired protein synthesis, or mechanical stress, they release more EVs to initiate compensatory mechanisms to survive102 (Figures 1 and 4). Cancer-derived EVs provide an intercellular exchange of important cellular cargoes such as nucleotides, nucleic acids, miRNAs, proteins, and secreted metabolites. The secretion of exosomes is a strategy developed by cancer cells to escape from the killing mechanism by our body’s immune system.103 Since mitochondrial components have substantial similarity with bacterial molecules, they can be treated with crucial intermediates of cellular signaling pathways that promote chronic inflammation and immune response. The reports found that plasma-derived EVs carry mtDNA and trigger an inflammatory response in macrophages through the TLR9-NF-κB pathway, making the TME present an immunosuppressive state to promote tumor progression.14 The tumor-derived EVs modulated by mitochondria undergo a significant change in the cargo selection and quantitative secretion, driving adaptation toward host immunosurveillance evasion.104 In addition to mtDAMPs, mitochondrial components and the whole mitochondria in the EVs can be considered as important biomarkers to understand the disease state and its role in immune evasion. Exosomes containing mitochondrial pertinent proteins like humanin, VDAC, and transcription factor A protein were rich in the plasma of patients rather than exosomes from neuroblastoma. Recently, EVs transmitting mitochondria from mesenchymal stromal cells to macrophages cause IL-4-induced anti-inflammatory macrophage polarization through the promotion of OXPHOS.105,106 Modulation in the mitochondrial activities like ROS, metabolism, and dynamics in the immune cells or in circulating EVs contributing to immune suppression could be targeted clinically. Therefore, a more complete analysis of EV-containing mitochondria is required to determine the exact nature of the EV content under different conditions. EVs can accommodate both damaged and functional mitochondria in their cargo population.107 The best example is LPS-induced mitochondrial damage in monocytes causes the damaged mitochondria to transfer to the endothelial cells via EVs and induces mtROS leading to the higher secretion of tumor necrosis factor (TNF) and type I interferon (IFN).108 In this way, the mitochondria enriched in exosomes of pro-inflammatory HLA-DR+ subsets of airway myeloid-derived regulatory cells (MDRCs) are important for T cell regulation.109 The pancreatic-cancer-derived exosomes downregulated the expression of HLA-DR, major histocompatibility complex (MHC) II cell surface receptor, and thereby induced arginase and ROS in monocytes.110 A wide array of studies on multiple tumors have shown that the level of PD-L1 on exosomes compromises the efficacy of immunotherapy. The exosome enhanced an increase in PD-L1 expression in the TME through HGMB1-mediated mTORC1-P70S6K signaling and RICTOR-driven glutamine metabolism.111 Recently, exosomes purified from the plasma of diverse cancer patients showed PD-L1 activation in the supernatants of various cancer cell lines. However, the detailed role of mitochondrial components in the EVs in relation to immunological relevance was certainly unclear.

Mitochondria-derived peptide for immune activity regulation

In tumor cells, neoantigens can be generated through mutations and different modifications of mtDNA, and via their cellular localization and post-translational modifications (PTMs), mutated peptides become immunogenic. The major types of PTMs including peptide oxidation and citrullination112,113 have been proposed as having the potential to generate neoantigens to induce immunity in cancer therapy. For example, the main sources of ROS are respiratory complexes I and III in the mitochondrial ETC2 and may also affect the oxidation state of peptide antigens that may increase interaction with specific TCRs.114 Some clues have shown that the transfer of mitochondria/mitochondrial proteins of tumor may involve tunneling nanotubes (TNTs),115 extracellular vesicle uptake,116 mitochondria-derived vesicles (MDVs),117,118 and mitochondrial-derived peptides (MDPs).119 It has been hypothesized that mutant mitochondrial proteins may be released into the cytoplasm, processed by the proteasome, translocated into the endoplasmic reticulum, and presented by MHC class I molecules.120 Some evidences have also suggested that mitophagy may also be involved in the presentation of mitochondrial antigens.18,121

Mitochondrial-derived peptides (MDPs) are functional microproteins encoded by mitochondrial DNA containing small open reading frames (sORFs).119 MDPs are novel peptides composed of mtDNA and sORFs. They are abundantly distributed in various tissues and use endocrine or paracrine to protect cells from mitochondrial dysfunction and stress by regulating cellular inflammation, metabolism, and survival. At present, at least 10 MDPs have been discovered in the human body. The first is the mitochondrial microbial protein Humanin (HN)122,123 to follow the mitochondrial ORF of the 12S rRNA type-c (MOTS-c),124 small humanin-like peptides 1 to 6 (SHLP1-6), small human mitochondrial ORF over serine tRNA (SHMOOSE), Gau (genes widely present in mtDNA), etc. SHLP3 can significantly increase interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) to inhibit inflammation.125 MOTS-c is a regulator of energy metabolism, which can activate AMPK, increase oxidized fatty acids to inhibit oxidative respiration, and inhibit the release of pro-inflammatory factors and adhesion molecules by inhibiting NF-kB.126 MDP is a brand new peptide or neoantigen, which is involved in mechanisms such as oxidative stress, ER stress, apoptosis, metabolism, and mitophagy by mitochondrial DNA expression, which can easily become a future biomarker and therapeutic target.

The translational significance of mitochondrial modulation in cancer immunotherapy

Recent new observation indicates that tumor not only interacts with a network of surrounding cells but also affects distant organs that in turn may affect primary or secondary tumor development, thus supporting the view that cancer is a systemic disease. Now immunotherapy as a revolutionary treatment of cancer has been emerging to treat or control cancer, which is absolutely considered as a systematic treatment and perfectly matches the systematic characteristics of tumor. However, the response and efficacy to cancer immunotherapy, e.g., anti-PD-1, are not expected and have only 10%–30% response rates in solid tumors. The response is heavily influenced by their status of TME, for example, an immunosuppressive TME. Manipulating the TME directly increases the anti-tumor effect and reverses the resistance of immunotherapy. In a chronic inflammation TME, tumor cells try to balance the lethal level of ROS in tumor cells by regulating several protective pathways as survival strategies.8,30 Here, we will focus on the translational and clinical significance of mitochondrial modulation that combines chemo/radiotherapy and immunotherapy against the survival strategies of cancer cells.

Mitochondria, as metabolic master cells, play a crucial role in the redox maintenance and establishment of immune responses.6,13 The mitochondrial OXPHOS system is the production of ATP biochemical pathway, and it is a serious therapeutic target in many cancer models. For example, Biguanides, including metformin and phenformin, inhibit the respiratory complex I of the ETC.127 In addition to targeting mitochondrial ETC, there are many papers that use mitochondrial-targeted designs or mitochondrial activity/metabolism to regulate PD-1 and enhance immunotherapy.14,128 For example, targeting ROS generation by mitochondria is an effective strategy for massive ICD bursts by inducing ATP and HMGB1 secretion and triggering tumor suppression by innate and adaptive immune systems in vivo.129

Beyond ROS modulation, TME-intrinsic and TOE mitochondrial metabolic activities have been taken as therapeutic targets.130 The mitochondria are a key metabolic organelle, providing not only ATP energy by the TCA cycle and oxidative phosphorylation (OXPHOS) but also many other essential materials to the cell growth. The compounds AGI-5198 and AGI6780 targeting specific oncometabolites, 2-hydroxyglutarate (R-2HG), specifically inhibit the mutant forms of IDH1 (isocitrate dehydrogenase 1) and IDH2, respectively, and have shown anti-cancer potential against glioblastoma and leukemia cells.131,132

The OXPHOS inhibitors, venetoclax plus azacitidine and Gamitrinib, and mitochondrial ETC inhibitors, metformin, deguelin, rotenone (complex I), and oligomycin and gboxin (complex V),133 were used in the recent clinical study of the patients with glioblastoma or cervical cancer. Moreover, it was found that several mitochondrial enzymes in lipid metabolism show a potential new vulnerabilities in the anti-cancer therapies. The link between fatty acid oxidation (FAO) and sensitivity to antitumor therapy draw much attention due to the key role of FAO in ATP production and redox balance. The notion of inhibiting carnitine palmitoyltransferase (CPT) was presented to increase sensitivity to chemotherapy and radiotherapy. In the TME, directly blocking succinate dehydrogenase (SDH) in activated T cells also repressed the efficacy of proliferation and pro-inflammatory activities,134 which implied that accumulated succinate could play inhibitory roles in immune cells, meanwhile increasing cancer cells malignancy. Further, another intermediate associated with the Krebs cycle that may play an immunomodulatory role is fumarate. Regarding the treatment of dimethyl fumarate (DMF), a drug known to treat multiple sclerosis and psoriasis, studies showed that peripheral blood mononuclear cells (PBMCs) isolated from psoriasis patients treated by DMF significantly decreased secretion of IFN-γ and GM-CSF and repressed mRNA level of IL-17 and IL-22.135 In total, targeting mitochondrial function is not only related to cancer but also closely related to immune cells in the TME, so that regulating mitochondrial ROS or targeting mitochondrial functions can enhance cancer immunotherapy or the treatment resistance strategies. From the TOE view, the essential role of whole-body metabolism in determining anti-cancer drug sensitivity and immunotherapy has also recently been revealed. For example, obesity serves as not only a risk factor in tumor initiation and progression but also a suppressor response to immunotherapies. The nutritional intervention approach is known to have a direct impact on the metabolism of both cancer and immune cells in the TME and TOE.63

ROS-induced mutational mtDNA can directly regulate the delivery of signal components through EVs modifying cellular homeostasis, resulting in mitochondrial retrograde signaling pathways that affect the mitochondrial metabolites to cellular injury. The secretion of exosomes or EVs modifies the mitochondrial function through the uptake of cargo by receptor cells such as tumor cells, immune cells, or another distant organ.

Since the difference in EVs from the origin tumor to the peripheral circulation, increasing studies described that EVs are considered as sources of tumor biomarkers in liquid biopsies.104,136 It is recognized that EVs are involved in the communication in cell-to-cell and organ-to-organ and are involved in the development of cancer disease.

Conclusion and perspectives

Cancer is a disease caused by abnormal cell growth and uncontrolled cell death with the ability to spread to other distant tissues. The point of view of cancer research is evolving from a “cancer-cell-centric” perspective to consider tumor as a network of surrounding cells, called a TME. With extravagance growth, some of the stress phenotypes detected in the TME are genome instability (replicative and mitotic stress), hypoxia (metabolic stress and sustained angiogenesis), and the increasing level of ROS (metabolic and mitochondrial stress). The increased ROS from cancer cells and various types of myeloid cells in the TME are a characteristic of chronic inflammation, which is intimately involved in cancer development and progression. Since the immunotherapy is emerging and a kind of concept of systemic therapy in whole body as well as the accumulating data indicate that the TME view is too narrow to accurately reflect the complexities of tumor, it is a perfect time to reconsider how to use systemic immunotherapy to treat or control cancer that is considered as a systemic disease. Recent basic and clinical study has proved that cancer progression is driven not only by genetic alterations but also by paracrine interactions within the TME and distant organs including the nervous system, microbiota, and immune system. The key issue of cancer immunotherapy is trying to keep the TME in the "hot" state and find the weakness of the non-oncogenic addiction for immunoescape, avoiding metastasis, and recurrence. Furthermore, we need to adopt a broader view with the concept of tumor micro- and macroenvironment (TM2E) or TOE (Figure 4).

Mitochondria play important roles in cell survival as they contribute to various cellular functions, including ATP production, apoptosis, calcium signaling, mitophagy, and signaling through mtROS. In fact, mitochondria are the major cellular source of ROS production. Low to moderate ROS levels promote cell proliferation, metastasis, angiogenesis, and inflammation. ROS in the TME are used by cancer cells, immunosuppressive macrophages, and DCs to create an immune tolerance environment for tumors, dampening the outcome of antitumor immunotherapy. In this review, since mitochondria are believed to be evolved from an endosymbiotic bacterium, we focus on the role of mitochondrial signaling, like microbiota, in the interaction with the components in the TME and TOE, in particular systemic immune components that regulate inflammation and effective cancer immunotherapy. In the TME and TOE, cancer cells interact with different components to escape from the immunosuppressive TM2E through mtROS-stimulated angiogenesis and migration, the secretion of inflammatory cytokines, and the secretion of EVs, mtDNA, and metabolites.

In summary, cancer immunotherapy is a kind of systemic therapy. The equilibrium of mitochondrial stress in the TME and TOE affects the immunosurveillance function, which will optimize the window to enhance the therapeutic efficacy of cancer immunotherapy. Rational combination of mitochondria-modulating agents and immunotherapy is emerging as a promising strategy of cancer treatment. With the help of vessel normalization, it will mitigate the excess ROS level and hypoxic resistance, which provides a route to drug delivery and immune cells. Further research is needed to provide insights on the role of mitochondria/ROS modulators to avoid the immunoescape and further recurrence and progression of cancer under an immunosuppressive TME and TOE.

Acknowledgments

This work was supported by grants from the 10.13039/100020595 National Science and Technology Council (NSTC110-2314-B-400-006- , NSTC112-2314-B-400-016- , NSTC113-2320-B-400 -018 -MY3, T-Star Cancer Center NSTC113-2634-F-039-001) , and the National Health Research Institutes (112/113CA-PP-06 ), Taiwan to A. Y.-L. Lee.

Author contributions

C.-L.K., Y.-C.L., and A.Y.-L.L. conceived the manuscript with input from all authors. The background was written by C.-L.K., A.P.B., and A.Y.-L. L.. Mitochondria as participants in causing inflammation and immunosuppression in the TME were written by C.-L.K. and Y.-C.L.. The interplay between mitochondrial calcium and cell death in immune regulation was written by A.P.B.. The effect of metabolism in mitochondria on the participants in the TME was written by Y.-C.L., Y.-Z.L., and H.-Y.C.. Mitochondrial dynamic change and mitochondrial quality control (MQC) in the immune response were written by Y. K.L. and A.P.B. Mitochondrial dynamics and immune metabolism was written by Y.-C.L., C.-L.K., H.-Y.C., and A.P.B.. Mitochondrial DNA (mtDNA) stability and the immune response were written by Y.K.L. Mitochondrial stress-induced secretion that contributes to immunoescape was written by Y.-C.L., H.-Y.C., and C.-L.K. The translational significance of mitochondrial modulation in cancer immunotherapy was written by H.-W.L. and A.Y.-L.L. Conclusions and Perspectives was written by A.Y.-L.L. and C.-L.K. Y.-C.L., and A.Y.-L.L. were responsible for the figures of the manuscript. C.-L.K. and A.Y.-L.L. were responsible for the final revision of the manuscript.

Declaration of interests

The authors have no conflicts of interest to declare.
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