Mitochondria in T‑cell tumor immunity and tumor therapies targeting mitochondria (Review)

Bereiter-Hahn J: Behavior of mitochondria in the living cell. Int Rev Cytol. 122:1–63. 1990. View Article : Google Scholar : PubMed/NCBI

Chan DC: Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol. 15:235–259. 2020. View Article : Google Scholar : PubMed/NCBI

Mills EL, Kelly B and O'Neill LAJ: Mitochondria are the powerhouses of immunity. Nat Immunol. 18:488–498. 2017. View Article : Google Scholar : PubMed/NCBI

Chandel NS: Mitochondria. Cold Spring Harbor Perspect Biol. 13:a0405432021. View Article : Google Scholar

Seo JH, Agarwal E, Bryant KG, Caino MC, Kim ET, Kossenkov AV, Tang HY, Languino LR, Gabrilovich DI, Cohen AR, et al: Syntaphilin ubiquitination regulates mitochondrial dynamics and tumor cell movements. Cancer Res. 78:4215–4228. 2018. View Article : Google Scholar : PubMed/NCBI

Wellen KE and Thompson CB: A two-way street: Reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol. 13:270–276. 2012. View Article : Google Scholar : PubMed/NCBI

Chan DC: Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol. 22:79–99. 2006. View Article : Google Scholar : PubMed/NCBI

Ikeda H, Kawase K, Nishi T, Watanabe T, Takenaga K, Inozume T, Ishino T, Aki S, Lin J, Kawashima S, et al: Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature. 638:225–236. 2025. View Article : Google Scholar : PubMed/NCBI

Suzuki J, Yamada T, Inoue K, Nabe S, Kuwahara M, Takemori N, Takemori A, Matsuda S, Kanoh M, Imai Y, et al: The tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic activation. Nat Commun. 9:32962018. View Article : Google Scholar : PubMed/NCBI

Harrington JS, Ryter SW, Plataki M, Price DR and Choi AMK: Mitochondria in health, disease, and aging. Physiol Rev. 103:2349–2422. 2023. View Article : Google Scholar : PubMed/NCBI

El Hiani Y, Ahidouch A, Lehen'kyi V, Hague F, Gouilleux F, Mentaverri R, Kamel S, Lassoued K, Brûlé G and Ouadid-Ahidouch H: Extracellular signal-regulated kinases 1 and 2 and TRPC1 channels are required for calcium-sensing receptor-stimulated MCF-7 breast cancer cell proliferation. Cell Physiol Biochem. 23:335–346. 2009. View Article : Google Scholar : PubMed/NCBI

DeBerardinis RJ and Chandel NS: Fundamentals of cancer metabolism. Sci Adv. 2:e16002002016. View Article : Google Scholar : PubMed/NCBI

Liu BH, Xu CZ, Liu Y, Lu ZL, Fu TL, Li GR, Deng Y, Luo GQ, Ding S, Li N and Geng Q: Mitochondrial quality control in human health and disease. Mil Med Res. 11:322024.PubMed/NCBI

Vodnala SK, Eil R, Kishton RJ, Sukumar M, Yamamoto TN, Ha NH, Lee PH, Shin M, Patel SJ, Yu Z, et al: T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science. 363:eaau01352019. View Article : Google Scholar : PubMed/NCBI

Lyssiotis CA and Kimmelman AC: Metabolic interactions in the tumor microenvironment. Trends Cell Biol. 27:863–875. 2017. View Article : Google Scholar : PubMed/NCBI

Scharping NE, Rivadeneira DB, Menk AV, Vignali PDA, Ford BR, Rittenhouse NL, Peralta R, Wang Y, Wang Y, DePeaux K, et al: Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol. 22:205–215. 2021. View Article : Google Scholar : PubMed/NCBI

Yu YR, Imrichova H, Wang H, Chao T, Xiao Z, Gao M, Rincon-Restrepo M, Franco F, Genolet R, Cheng WC, et al: Disturbed mitochondrial dynamics in CD8⁺ TILs reinforce T cell exhaustion. Nat Immunol. 21:1540–1551. 2020. View Article : Google Scholar : PubMed/NCBI

Vardhana SA, Hwee MA, Berisa M, Wells DK, Yost KE, King B, Smith M, Herrera PS, Chang HY, Satpathy AT, et al: Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat Immunol. 21:1022–1033. 2020. View Article : Google Scholar : PubMed/NCBI

Yang MQ, Zhang SL, Sun L, Huang LT, Yu J, Zhang JH, Tian Y, Han CB and Ma JT: Targeting mitochondria: Restoring the antitumor efficacy of exhausted T cells. Mol Cancer. 23:2602024. View Article : Google Scholar : PubMed/NCBI

König T, Nolte H, Aaltonen MJ, Tatsuta T, Krols M, Stroh T, Langer T and McBride HM: MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control. Nat Cell Biol. 23:1271–1286. 2021. View Article : Google Scholar : PubMed/NCBI

Mangalhara KC, Varanasi SK, Johnson MA, Burns MJ, Rojas GR, Esparza Moltó PB, Sainz AG, Tadepalle N, Abbott KL, Mendiratta G, et al: Manipulating mitochondrial electron flow enhances tumor immunogenicity. Science. 381:1316–1323. 2023. View Article : Google Scholar : PubMed/NCBI

Sullivan LB, Gui DY and Vander Heiden MG: Altered metabolite levels in cancer: Implications for tumour biology and cancer therapy. Nat Rev Cancer. 16:680–693. 2016. View Article : Google Scholar : PubMed/NCBI

De Martino M, Rathmell JC, Galluzzi L and Vanpouille-Box C: Cancer cell metabolism and antitumour immunity. Nat Rev Immunol. 24:654–669. 2024. View Article : Google Scholar : PubMed/NCBI

Tian W, Liu Y, Cao C, Zeng Y, Pan Y, Liu X, Peng Y and Wu F: Chronic stress: Impacts on tumor microenvironment and implications for anti-cancer treatments. Front Cell Dev Biol. 9:7770182021. View Article : Google Scholar : PubMed/NCBI

Lei Y, Liao F, Tian Y, Wang Y, Xia F and Wang J: Investigating the crosstalk between chronic stress and immune cells: Implications for enhanced cancer therapy. Front Neurosci. 17:13211762023. View Article : Google Scholar : PubMed/NCBI

Liu Y, Tian S, Ning B, Huang T, Li Y and Wei Y: Stress and cancer: The mechanisms of immune dysregulation and management. Front Immunol. 13:10322942022. View Article : Google Scholar : PubMed/NCBI

Kawano I, Bazila B, Ježek P and Dlasková A: Mitochondrial dynamics and cristae shape changes during metabolic reprogramming. Antioxid Redox Signaling. 39:684–707. 2023. View Article : Google Scholar

Xu X, Araki K, Li S, Han JH, Ye L, Tan WG, Konieczny BT, Bruinsma MW, Martinez J, Pearce EL, et al: Autophagy is essential for effector CD8(+) T cell survival and memory formation. Nat Immunol. 15:1152–1161. 2014. View Article : Google Scholar : PubMed/NCBI

Wu H, Zhao X, Hochrein SM, Eckstein M, Gubert GF, Knöpper K, Mansilla AM, Öner A, Doucet-Ladevèze R, Schmitz W, et al: Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming. Nat Commun. 14:68582023. View Article : Google Scholar : PubMed/NCBI

Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O'Sullivan D, Huang SC, van der Windt GJ, Blagih J, Qiu J, et al: Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 153:1239–1251. 2013. View Article : Google Scholar : PubMed/NCBI

Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A, Lovitch SB, Dephoure N, Satterstrom FK, Sheffer M, Spinelli JB, et al: Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab. 24:104–117. 2016. View Article : Google Scholar : PubMed/NCBI

Guerrero JA, Klysz DD, Chen Y, Malipatlolla M, Lone J, Fowler C, Stuani L, May A, Bashti M, Xu P, et al: GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency. Nat Commun. 15:86582024. View Article : Google Scholar : PubMed/NCBI

Ramstead AG, Wallace JA, Lee SH, Bauer KM, Tang WW, Ekiz HA, Lane TE, Cluntun AA, Bettini ML, Round JL, et al: Mitochondrial pyruvate carrier 1 promotes peripheral T cell homeostasis through metabolic regulation of thymic development. Cell Rep. 30:2889–2899.e6. 2020. View Article : Google Scholar : PubMed/NCBI

Christie DA, Kirchhof MG, Vardhana S, Dustin ML and Madrenas J: Mitochondrial and plasma membrane pools of stomatin-like protein 2 coalesce at the immunological synapse during T cell activation. PLoS One. 7:e371442012. View Article : Google Scholar : PubMed/NCBI

Fan X, Yang M, Lang Y, Lu S, Kong Z, Gao Y, Shen N, Zhang D and Lv Z: Mitochondrial metabolic reprogramming in diabetic kidney disease. Cell Death Dis. 15:4422024. View Article : Google Scholar : PubMed/NCBI

MacIver NJ, Michalek RD and Rathmell JC: Metabolic regulation of T lymphocytes. Annu Rev Immunol. 31:259–283. 2013. View Article : Google Scholar : PubMed/NCBI

Chapman NM and Chi H: Hallmarks of T-cell exit from quiescence. Cancer Immunol Res. 6:502–508. 2018. View Article : Google Scholar : PubMed/NCBI

Mescher MF, Curtsinger JM, Agarwal P, Casey KA, Gerner M, Hammerbeck CD, Popescu F and Xiao Z: Signals required for programming effector and memory development by CD8+ T cells. Immunol Rev. 211:81–92. 2006. View Article : Google Scholar : PubMed/NCBI

Makowski L, Chaib M and Rathmell JC: Immunometabolism: From basic mechanisms to translation. Immunol Rev. 295:5–14. 2020. View Article : Google Scholar : PubMed/NCBI

Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J and Green DR: The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 35:871–882. 2011. View Article : Google Scholar : PubMed/NCBI

Vaeth M, Maus M, Klein-Hessling S, Freinkman E, Yang J, Eckstein M, Cameron S, Turvey SE, Serfling E, Berberich-Siebelt F, et al: Store-operated Ca2⁺ entry controls clonal expansion of T cells through metabolic reprogramming. Immunity. 47:664–679.e6. 2017. View Article : Google Scholar : PubMed/NCBI

Stirnweiss A, Hartig R, Gieseler S, Lindquist JA, Reichardt P, Philipsen L, Simeoni L, Poltorak M, Merten C, Zuschratter W, et al: T cell activation results in conformational changes in the Src family kinase Lck to induce its activation. Sci Signaling. 6:ra132013. View Article : Google Scholar : PubMed/NCBI

Schwindling C, Quintana A, Krause E and Hoth M: Mitochondria positioning controls local calcium influx in T cells. J Immunol. 184:184–190. 2010. View Article : Google Scholar : PubMed/NCBI

Velnati S, Massarotti A, Antona A, Talmon M, Fresu LG, Galetto AS, Capello D, Bertoni A, Mercalli V, Graziani A, et al: Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors. J Enzyme Inhib Med Chem. 35:96–108. 2020. View Article : Google Scholar : PubMed/NCBI

Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP and Ahmed R: mTOR regulates memory CD8 T-cell differentiation. Nature. 460:108–112. 2009. View Article : Google Scholar : PubMed/NCBI

Klemm F, Maas RR, Bowman RL, Kornete M, Soukup K, Nassiri S, Brouland JP, Iacobuzio-Donahue CA, Brennan C, Tabar V, et al: Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell. 181:1643–1660.e17. 2020. View Article : Google Scholar : PubMed/NCBI

Cabrita R, Lauss M, Sanna A, Donia M, Skaarup Larsen M, Mitra S, Johansson I, Phung B, Harbst K, Vallon-Christersson J, et al: Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 577:561–565. 2020. View Article : Google Scholar : PubMed/NCBI

Connolly KA, Kuchroo M, Venkat A, Khatun A, Wang J, William I, Hornick NI, Fitzgerald BL, Damo M, Kasmani MY, et al: A reservoir of stem-like CD8⁺ T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response. Sci Immunol. 6:eabg78362021. View Article : Google Scholar : PubMed/NCBI

Prokhnevska N, Cardenas MA, Valanparambil RM, Sobierajska E, Barwick BG, Jansen C, Reyes Moon A, Gregorova P, delBalzo L, Greenwald R, et al: CD8⁺ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor. Immunity. 56:107–124.e5. 2023. View Article : Google Scholar : PubMed/NCBI

Nagasaki J, Inozume T, Sax N, Ariyasu R, Ishikawa M, Yamashita K, Kawazu M, Ueno T, Irie T, Tanji E, et al: PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes. Cell Rep. 38:1103312022. View Article : Google Scholar : PubMed/NCBI

Pai JA, Hellmann MD, Sauter JL, Mattar M, Rizvi H, Woo HJ, Shah N, Nguyen EM, Uddin FZ, Quintanal-Villalonga A, et al: Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade. Cancer Cell. 41:776–790.e7. 2023. View Article : Google Scholar : PubMed/NCBI

Liang H, Huang J, Li H, He W, Ao X, Xie Z, Chen Y, Lv Z, Zhang L, Zhong Y, et al: Spatial proximity of CD8⁺ T cells to tumor cells predicts neoadjuvant therapy efficacy in breast cancer. NPJ Breast Cancer. 11:132025. View Article : Google Scholar : PubMed/NCBI

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, et al: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 313:1960–1964. 2006. View Article : Google Scholar : PubMed/NCBI

Pagès F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, Lugli A, Zlobec I, Rau TT, Berger MD, et al: International validation of the consensus Immunoscore for the classification of colon cancer: A prognostic and accuracy study. Lancet. 391:2128–2139. 2018. View Article : Google Scholar : PubMed/NCBI

Angell HK, Bruni D, Barrett JC, Herbst R and Galon J: The immunoscore: Colon cancer and beyond. Clin Cancer Res. 26:332–339. 2020. View Article : Google Scholar : PubMed/NCBI

Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, Tsao HW, Godec J, LaFleur MW, Brown FD, et al: The epigenetic landscape of T cell exhaustion. Science. 354:1165–1169. 2016. View Article : Google Scholar : PubMed/NCBI

Reina-Campos M, Scharping NE and Goldrath AW: CD8⁺ T cell metabolism in infection and cancer. Nat Rev Immunol. 21:718–738. 2021. View Article : Google Scholar : PubMed/NCBI

Zhu J and Thompson CB: Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol. 20:436–450. 2019. View Article : Google Scholar : PubMed/NCBI

Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, et al: LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24:657–671. 2016. View Article : Google Scholar : PubMed/NCBI

Vigano S, Alatzoglou D, Irving M, Ménétrier-Caux C, Caux C, Romero P and Coukos G: Targeting adenosine in cancer immunotherapy to enhance T-cell function. Front Immunol. 10:9252019. View Article : Google Scholar : PubMed/NCBI

Qin M, Hamanishi J, Ukita M, Yamanoi K, Takamatsu S, Abiko K, Murakami R, Miyamoto T, Suzuki H, Ueda A, et al: Tertiary lymphoid structures are associated with favorable survival outcomes in patients with endometrial cancer. Cancer Immunol Immunother. 71:1431–1442. 2022. View Article : Google Scholar : PubMed/NCBI

Zhang MJ, Wen Y and Sun ZJ: The impact of metabolic reprogramming on tertiary lymphoid structure formation: Enhancing cancer immunotherapy. BMC Med. 23:2172025. View Article : Google Scholar : PubMed/NCBI

Jia D, Wang Q, Qi Y, Jiang Y, He J, Lin Y, Sun Y, Xu J, Chen W, Fan L, et al: Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer. Cell. 187:1651–1665.e21. 2024. View Article : Google Scholar : PubMed/NCBI

Guo Y, Xie YQ, Gao M, Zhao Y, Franco F, Wenes M, Siddiqui I, Bevilacqua A, Wang H, Yang H, et al: Metabolic reprogramming of terminally exhausted CD8⁺ T cells by IL-10 enhances anti-tumor immunity. Nat Immunol. 22:746–756. 2021. View Article : Google Scholar : PubMed/NCBI

Sukumar M, Kishton RJ and Restifo NP: Metabolic repro-graming of anti-tumor immunity. Curr Opin Immunol. 46:14–22. 2017. View Article : Google Scholar : PubMed/NCBI

Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, Ferris RL and Delgoffe GM: The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity. 45:374–388. 2016. View Article : Google Scholar : PubMed/NCBI

Dumauthioz N, Tschumi B, Wenes M, Marti B, Wang H, Franco F, Li W, Lopez-Mejia IC, Fajas L, Ho PC, et al: Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity. Cell Mol Immunol. 18:1761–1771. 2021. View Article : Google Scholar : PubMed/NCBI

Song M, Sandoval TA, Chae CS, Chopra S, Tan C, Rutkowski MR, Raundhal M, Chaurio RA, Payne KK, Konrad C, et al: IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature. 562:423–428. 2018. View Article : Google Scholar : PubMed/NCBI

Cham CM, Driessens G, O'Keefe JP and Gajewski TF: Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells. Eur J Immunol. 38:2438–2450. 2008. View Article : Google Scholar : PubMed/NCBI

Wenes M, Jaccard A, Wyss T, Maldonado-Pérez N, Teoh ST, Lepez A, Renaud F, Franco F, Waridel P, Yacoub Maroun C, et al: The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function. Cell Metab. 34:731–746.e9. 2022. View Article : Google Scholar : PubMed/NCBI

Nava Lauson CB, Tiberti S, Corsetto PA, Conte F, Tyagi P, Machwirth M, Ebert S, Loffreda A, Scheller L, Sheta D, et al: Linoleic acid potentiates CD8⁺ T cell metabolic fitness and antitumor immunity. Cell Metab. 35:633–650.e9. 2023. View Article : Google Scholar : PubMed/NCBI

Tang Y, Chen Z, Zuo Q and Kang Y: Regulation of CD8+ T cells by lipid metabolism in cancer progression. Cell Mol Immunol. 21:1215–1230. 2024. View Article : Google Scholar : PubMed/NCBI

Pauken KE and Wherry EJ: Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36:265–276. 2015. View Article : Google Scholar : PubMed/NCBI

Greenwald RJ, Freeman GJ and Sharpe AH: The B7 family revisited. Annu Rev Immunol. 23:515–548. 2005. View Article : Google Scholar : PubMed/NCBI

Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, et al: PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 6:66922015. View Article : Google Scholar : PubMed/NCBI

Boussiotis VA and Patsoukis N: Effects of PD-1 signaling on immunometabolic reprogramming. Immunometabolism. 4:e2200072022. View Article : Google Scholar : PubMed/NCBI

Baldanzi G: Immune checkpoint receptors signaling in T cells. Int J Mol Sci. 23:35292022. View Article : Google Scholar : PubMed/NCBI

Zhao M, Yuan H, Yang G, Wang Y, Bu Y, Zhang H, Zhao L, Lv P, Yun H, Geng Y, et al: Tumour cell-expressed PD-L1 reprograms lipid metabolism via EGFR/ITGB4/SREBP1c signalling in liver cancer. JHEP Rep. 6:1010092024. View Article : Google Scholar : PubMed/NCBI

Ma F, Liu X, Zhang Y, Tao Y, Zhao L, Abusalamah H, Huffman C, Harbison RA, Puram SV, Wang Y and Peng G: Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming. Sci Transl Med. 17:eadm72692025. View Article : Google Scholar : PubMed/NCBI

Ping Y, Shan J, Qin H, Li F, Qu J, Guo R, Han D, Jing W, Liu Y, Liu J, et al: PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8⁺ T cell ferroptosis. Immunity. 57:2122–2139.e9. 2024. View Article : Google Scholar : PubMed/NCBI

Alsayyah C, Singh MK, Morcillo-Parra MA, Cavellini L, Shai N, Schmitt C, Schuldiner M, Zalckvar E, Mallet A, Belgareh-Touzé N, et al: Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion. PLoS Biol. 22:e30026022024. View Article : Google Scholar : PubMed/NCBI

Sandoval H, Thiagarajan P, Dasgupta SK, Schumacher A, Prchal JT, Chen M and Wang J: Essential role for Nix in autophagic maturation of erythroid cells. Nature. 454:232–235. 2008. View Article : Google Scholar : PubMed/NCBI

Lu Y, Li Z, Zhang S, Zhang T, Liu Y and Zhang L: Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation. Theranostics. 13:736–766. 2023. View Article : Google Scholar : PubMed/NCBI

Wang S, Long H, Hou L, Feng B, Ma Z, Wu Y, Zeng Y, Cai J, Zhang DW and Zhao G: The mitophagy pathway and its implications in human diseases. Signal Transduction Targeted Ther. 8:3042023. View Article : Google Scholar : PubMed/NCBI

White E, Lattime EC and Guo JY: Autophagy regulates stress responses, metabolism, and anticancer immunity. Trends Cancer. 7:778–789. 2021. View Article : Google Scholar : PubMed/NCBI

Silwal P, Kim JK, Kim YJ and Jo EK: Mitochondrial reactive oxygen species: Double-edged weapon in host defense and pathological inflammation during infection. Front Immunol. 11:16492020. View Article : Google Scholar : PubMed/NCBI

Mougiakakos D, Johansson CC, Jitschin R, Böttcher M and Kiessling R: Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers enhanced tolerance to oxidative stress. Blood. 117:857–861. 2011. View Article : Google Scholar : PubMed/NCBI

Mougiakakos D, Johansson CC and Kiessling R: Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. Blood. 113:3542–3545. 2009. View Article : Google Scholar : PubMed/NCBI

Seledtsov VI, Goncharov AG and Seledtsova GV: Clinically feasible approaches to potentiating cancer cell-based immunotherapies. Hum Vaccin Immunother. 11:851–869. 2015. View Article : Google Scholar : PubMed/NCBI

Weiskopf D, Schwanninger A, Weinberger B, Almanzar G, Parson W, Buus S, Lindner H and Grubeck-Loebenstein B: Oxidative stress can alter the antigenicity of immunodominant peptides. J Leukocyte Biol. 87:165–172. 2010. View Article : Google Scholar : PubMed/NCBI

Cheung EC and Vousden KH: The role of ROS in tumour development and progression. Nat Rev Cancer. 22:280–297. 2022. View Article : Google Scholar : PubMed/NCBI

Hildeman DA, Mitchell T, Teague TK, Henson P, Day BJ, Kappler J and Marrack PC: Reactive oxygen species regulate activation-induced T cell apoptosis. Immunity. 10:735–744. 1999. View Article : Google Scholar : PubMed/NCBI

Bailly C: Regulation of PD-L1 expression on cancer cells with ROS-modulating drugs. Life Sci. 246:1174032020. View Article : Google Scholar : PubMed/NCBI

Kuo CL, Ponneri Babuharisankar A, Lin YC, Lien HW, Lo YK, Chou HY, Tangeda V, Cheng LC, Cheng AN and Lee AY: Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: Foe or friend? J Biomed Sci. 29:742022. View Article : Google Scholar : PubMed/NCBI

Deng H, Yang W, Zhou Z, Tian R, Lin L, Ma Y, Song J and Chen X: Targeted scavenging of extracellular ROS relieves suppressive immunogenic cell death. Nat Commun. 11:49512020. View Article : Google Scholar : PubMed/NCBI

Kurniawan H, Franchina DG, Guerra L, Bonetti L, -Baguet LS, Grusdat M, Schlicker L, Hunewald O, Dostert C, Merz MP, et al: Glutathione restricts serine metabolism to preserve regulatory T cell function. Cell Metab. 31:920–936.e7. 2020. View Article : Google Scholar : PubMed/NCBI

Kyriakoudi S, Drousiotou A and Petrou PP: When the balance tips: Dysregulation of mitochondrial dynamics as a culprit in disease. Int J Mol Sci. 22:46172021. View Article : Google Scholar : PubMed/NCBI

de Brito OM and Scorrano L: Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 456:605–610. 2008. View Article : Google Scholar : PubMed/NCBI

Buck MD, O'Sullivan D, Klein Geltink RI, Curtis JD, Chang CH, Sanin DE, Qiu J, Kretz O, Braas D, van der Windt GJ, et al: Mitochondrial dynamics controls T cell fate through metabolic programming. Cell. 166:63–76. 2016. View Article : Google Scholar : PubMed/NCBI

Picca A, Mankowski RT, Burman JL, Donisi L, Kim JS, Marzetti E and Leeuwenburgh C: Mitochondrial quality control mechanisms as molecular targets in cardiac ageing. Nat Rev Cardiol. 15:543–554. 2018. View Article : Google Scholar : PubMed/NCBI

Yang JF, Xing X, Luo L, Zhou XW, Feng JX, Huang KB, Liu H, Jin S, Liu YN, Zhang SH, et al: Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8⁺ T cell metabolic fitness and function in tumors. Sci Immunol. 8:eabq24242023. View Article : Google Scholar : PubMed/NCBI

Tilokani L, Nagashima S, Paupe V and Prudent J: Mitochondrial dynamics: Overview of molecular mechanisms. Essays Biochem. 62:341–360. 2018. View Article : Google Scholar : PubMed/NCBI

Menk AV, Scharping NE, Rivadeneira DB, Calderon MJ, Watson MJ, Dunstane D, Watkins SC and Delgoffe GM: 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J Exp Med. 215:1091–1100. 2018. View Article : Google Scholar : PubMed/NCBI

Hu C, Huang Y and Li L: Drp1-dependent mitochondrial fission plays critical roles in physiological and pathological progresses in mammals. Int J Mol Sci. 18:1442017. View Article : Google Scholar : PubMed/NCBI

Cereghetti GM, Stangherlin A, Martins De Brito O, Chang CR, Blackstone C, Bernardi P and Scorrano L: Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci USA. 105:15803–15808. 2008. View Article : Google Scholar : PubMed/NCBI

Smith-Garvin JE, Koretzky GA and Jordan MS: T cell activation. Annu Rev Immunol. 27:591–619. 2009. View Article : Google Scholar : PubMed/NCBI

Woehrle T, Ledderose C, Rink J, Slubowski C and Junger WG: Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation. Purinergic Signalling. 15:127–137. 2019. View Article : Google Scholar : PubMed/NCBI

Ledderose C, Bromberger S, Slubowski CJ, Sueyoshi K and Junger WG: Frontline science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse. J Leukocyte Biol. 109:497–508. 2021. View Article : Google Scholar : PubMed/NCBI

Quintana A, Schwindling C, Wenning AS, Becherer U, Rettig J, Schwarz EC and Hoth M: T cell activation requires mitochondrial translocation to the immunological synapse. Proc Natl Acad Sci USA. 104:14418–14423. 2007. View Article : Google Scholar : PubMed/NCBI

Simula L, Pacella I, Colamatteo A, Procaccini C, Cancila V, Bordi M, Tregnago C, Corrado M, Pigazzi M, Barnaba V, et al: Drp1 controls effective T cell immune-surveillance by regulating T cell migration, proliferation, and cMyc-dependent metabolic reprogramming. Cell Rep. 25:3059–3073.e10. 2018. View Article : Google Scholar : PubMed/NCBI

Mohammadalipour A, Dumbali SP and Wenzel PL: Mitochondrial transfer and regulators of mesenchymal stromal cell function and therapeutic efficacy. Front Cell Dev Biol. 8:6032922020. View Article : Google Scholar : PubMed/NCBI

Lambeth DO: What is the function of GTP produced in the Krebs citric acid cycle? IUBMB Life. 54:143–144. 2002.PubMed/NCBI

Saha T, Dash C, Jayabalan R, Khiste S, Kulkarni A, Kurmi K, Mondal J, Majumder PK, Bardia A, Jang HL and Sengupta S: Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nat Nanotechnol. 17:98–106. 2022. View Article : Google Scholar : PubMed/NCBI

Baldwin JG, Heuser-Loy C, Saha T, Schelker RC, Slavkovic-Lukic D, Strieder N, Hernandez-Lopez I, Rana N, Barden M, Mastrogiovanni F, et al: Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy. Cell. 187:6614–6630.e21. 2024. View Article : Google Scholar : PubMed/NCBI

Monaghan RM and Whitmarsh AJ: Mitochondrial proteins moonlighting in the nucleus. Trends Biochem Sci. 40:728–735. 2015. View Article : Google Scholar : PubMed/NCBI

English J, Son JM, Cardamone MD, Lee C and Perissi V: Decoding the rosetta stone of mitonuclear communication. Pharmacol Res. 161:1051612020. View Article : Google Scholar : PubMed/NCBI

Quirós PM, Mottis A and Auwerx J: Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol. 17:213–226. 2016. View Article : Google Scholar : PubMed/NCBI

Whelan SP and Zuckerbraun BS: Mitochondrial signaling: Forwards, backwards, and in between. Oxid Med Cell Longev. 2013:3516132013. View Article : Google Scholar : PubMed/NCBI

Jazwinski SM: The retrograde response: A conserved compensatory reaction to damage from within and from without. Prog Mol Biol Transl Sci. 127:133–154. 2014. View Article : Google Scholar : PubMed/NCBI

Walker BR and Moraes CT: Nuclear-mitochondrial interactions. Biomolecules. 12:4272022. View Article : Google Scholar : PubMed/NCBI

Ju YS, Alexandrov LB, Gerstung M, Martincorena I, Nik-Zainal S, Ramakrishna M, Davies HR, Papaemmanuil E, Gundem G, Shlien A, et al: Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. Elife. 3:e029352014. View Article : Google Scholar : PubMed/NCBI

Chen S, Liao Z and Xu P: Mitochondrial control of innate immune responses. Front Immunol. 14:11662142023. View Article : Google Scholar : PubMed/NCBI

Riley JS and Tait SW: Mitochondrial DNA in inflammation and immunity. EMBO Rep. 21:e497992020. View Article : Google Scholar : PubMed/NCBI

Lin Y, Yang B, Huang Y, Zhang Y, Jiang Y, Ma L and Shen YQ: Mitochondrial DNA-targeted therapy: A novel approach to combat cancer. Cell Insight. 2:1001132023. View Article : Google Scholar : PubMed/NCBI

West AP, Shadel GS and Ghosh S: Mitochondria in innate immune responses. Nat Rev Immunol. 11:389–402. 2011. View Article : Google Scholar : PubMed/NCBI

West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, Bestwick M, Duguay BA, Raimundo N, MacDuff DA, et al: Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 520:553–557. 2015. View Article : Google Scholar : PubMed/NCBI

Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, et al: Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 36:401–414. 2012. View Article : Google Scholar : PubMed/NCBI

De Gaetano A, Solodka K, Zanini G, Selleri V, Mattioli AV, Nasi M and Pinti M: Molecular mechanisms of mtDNA-mediated inflammation. Cells. 10:28982021. View Article : Google Scholar : PubMed/NCBI

Wang X, Zhang H, Wang Y, Bramasole L, Guo K, Mourtada F, Meul T, Hu Q, Viteri V, Kammerl I, et al: DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity. EMBO J. 42:e1105972023. View Article : Google Scholar : PubMed/NCBI

Cheng AN, Cheng LC, Kuo CL, Lo YK, Chou HY, Chen CH, Wang YH, Chuang TH, Cheng SJ and Lee AY: Mitochondrial lon-induced mtDNA leakage contributes to PD-L1-mediated immunoescape via STING-IFN signaling and extracellular vesicles. J Immunother Cancer. 8:e0013722020. View Article : Google Scholar : PubMed/NCBI

Mahmood M, Liu EM, Shergold AL, Tolla E, Tait-Mulder J, Huerta-Uribe A, Shokry E, Young AL, Lilla S, Kim M, et al: Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma. Nat Cancer. 5:659–672. 2024. View Article : Google Scholar : PubMed/NCBI

Corrado M, Samardžić D, Giacomello M, Rana N, Pearce EL and Scorrano L: Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism. Cell Death Differ. 28:2194–2206. 2021. View Article : Google Scholar : PubMed/NCBI

Peng J, Hu X, Fan S, Zhou J, Ren S, Sun R and Chen Y, Shen X and Chen Y: Inhibition of mitochondrial biosynthesis using a ‘right-side-out’ membrane-camouflaged micelle to facilitate the therapeutic effects of shikonin on triple-negative breast cancer. Adv Healthc Mater. 11:e22007422022. View Article : Google Scholar : PubMed/NCBI

Gemta LF, Siska PJ, Nelson ME, Gao X, Liu X, Locasale JW, Yagita H, Slingluff CL Jr, Hoehn KL, Rathmell JC and Bullock TNJ: Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8⁺ T cells. Sci Immunol. 4:eaap95202019. View Article : Google Scholar : PubMed/NCBI

Al-Habsi M, Chamoto K, Matsumoto K, Nomura N, Zhang B, Sugiura Y, Sonomura K, Maharani A, Nakajima Y, Wu Y, et al: Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science. 378:eabj35102022. View Article : Google Scholar : PubMed/NCBI

Cronin SJF, Seehus C, Weidinger A, Talbot S, Reissig S, Seifert M, Pierson Y, McNeill E, Longhi MS, Turnes BL, et al: The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature. 563:564–568. 2018. View Article : Google Scholar : PubMed/NCBI

Malinee M, Pandian GN and Sugiyama H: Targeted epigenetic induction of mitochondrial biogenesis enhances antitumor immunity in mouse model. Cell Chem Biol. 29:463–475.e6. 2022. View Article : Google Scholar : PubMed/NCBI

Chamoto K, Chowdhury PS, Kumar A, Sonomura K, Matsuda F, Fagarasan S and Honjo T: Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci USA. 114:E761–E770. 2017. View Article : Google Scholar : PubMed/NCBI

Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, Filisio F, Giles-Davis W, Xu X, Karakousis GC, et al: Enhancing CD8⁺ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell. 32:377–391.e9. 2017. View Article : Google Scholar : PubMed/NCBI

He J, Shangguan X, Zhou W, Cao Y, Zheng Q, Tu J, Hu G, Liang Z, Jiang C, Deng L, et al: Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development. Nat Commun. 12:43712021. View Article : Google Scholar : PubMed/NCBI

Yuan S, Sun R, Shi H, Chapman NM, Hu H, Guy C, Rankin S, Kc A, Palacios G, Meng X, et al: VDAC2 loss elicits tumour destruction and inflammation for cancer therapy. Nature. 640:1062–1071. 2025. View Article : Google Scholar : PubMed/NCBI

Liu YN, Yang JF, Huang DJ, Ni HH, Zhang CX, Zhang L, He J, Gu JM, Chen HX, Mai HQ, et al: Hypoxia induces mitochondrial defect that promotes T cell exhaustion in tumor microenvironment through MYC-regulated pathways. Front Immunol. 11:19062020. View Article : Google Scholar : PubMed/NCBI

Teijeira A, Labiano S, Garasa S, Etxeberria I, Santamaría E, Rouzaut A, Enamorado M, Azpilikueta A, Inoges S, Bolaños E, et al: Mitochondrial morphological and functional reprogramming following CD137 (4-1BB) costimulation. Cancer Immunol Res. 6:798–811. 2018. View Article : Google Scholar : PubMed/NCBI

Wan H, Xu B, Zhu N and Ren B: PGC-1α activator-induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer. Tumori. 106:55–63. 2020. View Article : Google Scholar : PubMed/NCBI

Chowdhury PS, Chamoto K, Kumar A and Honjo T: PPAR-induced fatty acid oxidation in T cells increases the number of tumor-reactive CD8⁺ T cells and facilitates anti-PD-1 therapy. Cancer Immunol Res. 6:1375–1387. 2018. View Article : Google Scholar : PubMed/NCBI

Bukoreshtliev NV, Wang X, Hodneland E, Gurke S, Barroso JFV and Gerdes HH: Selective block of tunneling nanotube (TNT) formation inhibits intercellular organelle transfer between PC12 cells. FEBS Lett. 583:1481–1488. 2009. View Article : Google Scholar : PubMed/NCBI

Liu K, Ji K, Guo L, Wu W, Lu H, Shan P and Yan C: Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia-reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvasc Res. 92:10–18. 2014. View Article : Google Scholar : PubMed/NCBI

Onfelt B, Nedvetzki S, Benninger RKP, Purbhoo MA, Sowinski S, Hume AN, Seabra MC, Neil MA, French PM and Davis DM: Structurally distinct membrane nanotubes between human macrophages support long-distance vesicular traffic or surfing of bacteria. J Immunol. 177:8476–8483. 2006. View Article : Google Scholar : PubMed/NCBI

Zhang H, Yu X, Ye J, Li H, Hu J, Tan Y, Fang Y, Akbay E, Yu F, Weng C, et al: Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution. Cancer Cell. 41:1788–1802.e10. 2023. View Article : Google Scholar : PubMed/NCBI

Pierini S, Fang C, Rafail S, Facciponte JG, Huang J, De Sanctis F, Morgan MA, Uribe-Herranz M, Tanyi JL and Facciabene A: A tumor mitochondria vaccine protects against experimental renal cell carcinoma. J Immunol. 195:4020–4027. 2015. View Article : Google Scholar : PubMed/NCBI

Shang L, Jiang X, Zhao X, Huang X, Wang X, Jiang X, Kong X, Yao M, Jiang S and Wong PP: Mitochondrial DNA-boosted dendritic cell-based nanovaccination triggers antitumor immunity in lung and pancreatic cancers. Cell Rep Med. 5:1016482024. View Article : Google Scholar : PubMed/NCBI

Mok BY, de Moraes MH, Zeng J, Bosch DE, Kotrys AV, Raguram A, Hsu F, Radey MC, Peterson SB, Mootha VK, et al: A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing. Nature. 583:631–637. 2020. View Article : Google Scholar : PubMed/NCBI

Fan Y, Xu W, Gao BQ, Qin H, Wu X, Wei J, Ni Q, Zhou L, Xiang J, Wu J, et al: Leveraging base excision repair for efficient adenine base editing of mitochondrial DNA. Nat Biotechnol. Mar 25–2025.(Epub ahead of print). View Article : Google Scholar

Guo Y, Zhang H, Yan C, Shen B, Zhang Y, Guo X, Sun S, Yu F, Yan J, Liu R, et al: Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction. Nat Chem Biol. 19:468–477. 2023. View Article : Google Scholar : PubMed/NCBI

Chen L, Fan Y, Jiang N, Huang X, Yu M, Zhang H, Xu Z, He D, Wang Y, Ding C, et al: An energy metabolism-engaged nanomedicine maintains mitochondrial homeostasis to alleviate cellular ageing. Nat Nanotechnol. 20:1332–1344. 2025. View Article : Google Scholar : PubMed/NCBI

Pan X, Wang Z, Tan M, Fu Z, Nie G and Wang H: Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers. Nat Nanotechnol. 20:947–958. 2025. View Article : Google Scholar : PubMed/NCBI

Lv Y, Song B, Yang G, Wang Y, Wu Z, Si M, Yang Z, Chen H, Liu C, Li M, et al: In situ transformable nanoparticle effectively suppresses bladder cancer by damaging mitochondria and blocking mitochondrial autophagy flux. Adv Sci (Weinh). 12:e24094252025. View Article : Google Scholar : PubMed/NCBI

Wang W, Yao SY, Luo J, Ding C, Huang Q, Yang Y, Shi Z, Lin J, Pan YC, Zeng X, et al: Engineered hypoxia-responsive albumin nanoparticles mediating mitophagy regulation for cancer therapy. Nat Commun. 16:5962025. View Article : Google Scholar : PubMed/NCBI

Liu J, Yan Y, Zhang Y, Pan X, Xia H, Zhou J, Wan F, Huang X, Zhang W, Zhang Q, et al: Lysosome-mitochondria cascade targeting nanoparticle drives robust pyroptosis for cancer immunotherapy. J Am Chem Soc. 146:34568–34582. 2024. View Article : Google Scholar : PubMed/NCBI

Pei D and Buyanova M: Overcoming endosomal entrapment in drug delivery. Bioconjug Chem. 30:273–283. 2019. View Article : Google Scholar : PubMed/NCBI

Goswami R, Jeon T, Nagaraj H, Zhai S and Rotello VM: Accessing intracellular targets through nanocarrier-mediated cytosolic protein delivery. Trends Pharmacol Sci. 41:743–754. 2020. View Article : Google Scholar : PubMed/NCBI

Kang H, Han M, Xue J, Baek Y, Chang J, Hu S, Nam H, Jo MJ, El Fakhri G, Hutchens MP, et al: Renal clearable nanochelators for iron overload therapy. Nat Commun. 10:51342019. View Article : Google Scholar : PubMed/NCBI

Feng K, Xu Z, Wang Y, Wu X, Xiong F, Ruan Y, Wu X, Ye L, Su D, Yu J and Sun X: Renal-clearable porous hollow copper iron oxide nanoparticles for trimodal chemodynamic-photothermal-chemo anti-tumor therapy. Nanoscale. 15:3188–3198. 2023. View Article : Google Scholar : PubMed/NCBI