Targeting organelle function in T cells for cancer immunotherapy

targeting-organelle-function-in-t-cells-for-cancer-immunotherapy
Targeting organelle function in T cells for cancer immunotherapy
  • Suomalainen, A. & Nunnari, J. Mitochondria at the crossroads of health and disease. Cell 187, 2601–2627 (2024).

    Article  CAS  PubMed  Google Scholar 

  • Steinert, E. M. et al. Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate. Nat. Immunol. 26, 1267–1274 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heuser, C., Renner, K., Kreutz, M. & Gattinoni, L. Targeting lactate metabolism for cancer immunotherapy — a matter of precision. Semin. Cancer Biol. 88, 32–45 (2023).

    Article  CAS  PubMed  Google Scholar 

  • Simula, L. et al. Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors. Nat. Commun. 15, 2203 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaymak, I. et al. Carbon source availability drives nutrient utilization in CD8+ T cells. Cell Metab. 34, 1298–1311.e6 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hunt, E. G. et al. Acetyl-CoA carboxylase obstructs CD8+ T cell lipid utilization in the tumor microenvironment. Cell Metab. 36, 969–983.e10 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma, S. et al. Targeting P4HA1 promotes CD8+ T cell progenitor expansion toward immune memory and systemic anti-tumor immunity. Cancer Cell 43, 213–231.e9 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Geiger, R. et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842.e13 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kishton, R. J., Sukumar, M. & Restifo, N. P. Arginine arms T cells to thrive and survive. Cell Metab. 24, 647–648 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martí i Líndez, A. A. et al. Mitochondrial arginase-2 is a cell-autonomous regulator of CD8+ T cell function and antitumor efficacy. JCI Insight 4, e132975 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy, M. P. & Siegel, R. M. Mitochondrial ROS fire up T cell activation. Immunity 38, 201–202 (2013).

    Article  CAS  PubMed  Google Scholar 

  • Scharping, N. E. et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22, 205–215 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu, Y.-R. et al. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat. Immunol. 21, 1540–1551 (2020). Seminal studies by Scharping et al. (2021) and Yu et al. (2020) were instrumental in shaping our understanding of the role of mitochondrial dysfunction in driving T cell exhaustion.

    Article  CAS  PubMed  Google Scholar 

  • Wu, H. et al. Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming. Nat. Commun. 14, 6858 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fisicaro, P. et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat. Med. 23, 327–336 (2017).

    Article  CAS  PubMed  Google Scholar 

  • Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374–388 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itoh, Y. et al. Mechanism of membrane-tethered mitochondrial protein synthesis. Science 371, 846–849 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lisci, M. et al. Mitochondrial translation is required for sustained killing by cytotoxic T cells. Science 374, eabe9977 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Almeida, L. et al. Ribosome-targeting antibiotics impair T cell effector function and ameliorate autoimmunity by blocking mitochondrial protein synthesis. Immunity 54, 68–83.e6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martínez-Reyes, I. & Chandel, N. S. Mitochondrial TCA cycle metabolites control physiology and disease. Nat. Commun. 11, 102 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  • Soriano-Baguet, L. & Brenner, D. Metabolism and epigenetics at the heart of T cell function. Trends Immunol. 44, 231–244 (2023).

    Article  CAS  PubMed  Google Scholar 

  • Tyrakis, P. A. et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540, 236–241 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minogue, E. et al. Glutarate regulates T cell metabolism and anti-tumour immunity. Nat. Metab. 5, 1747–1764 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ryu, K. W. et al. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria. Nature 635, 746–754 (2024). This study sheds light on how the machinery required for competing oxidative and reductive reactions in mitochondria is segregated into distinct mitochondrial populations under nutrient stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katajisto, P. et al. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science 348, 340–343 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hinge, A. et al. Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition. Cell Stem Cell 26, 420–430.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borsa, M. et al. Inheritance of old mitochondria controls early CD8+ T cell fate commitment and is regulated by autophagy. Preprint at bioRxiv https://doi.org/10.1101/2024.01.29.577412 (2024).

  • Adams, W. C. et al. Anabolism-associated mitochondrial stasis driving lymphocyte differentiation over self-renewal. Cell Rep. 17, 3142–3152 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu, X. et al. Autophagy is essential for effector CD8+ T cell survival and memory formation. Nat. Immunol. 15, 1152–1161 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwarz, D. S. & Blower, M. D. The endoplasmic reticulum: structure, function and response to cellular signaling. Cell. Mol. Life Sci. 73, 79–94 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Trebak, M. & Kinet, J. P. Calcium signalling in T cells. Nat. Rev. Immunol. 19, 154–169 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Araki, K. et al. Translation is actively regulated during the differentiation of CD8+ effector T cells. Nat. Immunol. 18, 1046–1057 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sinclair, L. V. & Cantrell, D. A. Protein synthesis and metabolism in T cells. Annu. Rev. Immunol. 43, 343–366 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Wolf, T. et al. Dynamics in protein translation sustaining T cell preparedness. Nat. Immunol. 21, 927–937 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Claiborne, M. D. et al. Persistent CAD activity in memory CD8+ T cells supports rRNA synthesis and ribosomal biogenesis required at rechallenge. Sci. Immunol. 7, eabh4271 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Todd, D. J., Lee, A.-H. & Glimcher, L. H. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat. Rev. Immunol. 8, 663–674 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Nair, K. A. & Liu, B. Navigating the landscape of the unfolded protein response in CD8+ T cells. Front. Immunol. 15, 1427859 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Correa-Medero, L. O. et al. ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection. Cell Rep. 43, 114156 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamimura, D. & Bevan, M. J. Endoplasmic reticulum stress regulator XBP-1 contributes to effector CD8+ T cell differentiation during acute infection. J. Immunol. 181, 5433–5441 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Cao, Y. et al. ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nat. Commun. 10, 1280 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Fernández-Alfara, M. et al. Antitumor T-cell function requires CPEB4-mediated adaptation to chronic endoplasmic reticulum stress. EMBO J. 42, e111494 (2023). This study elucidates how T cells use CPEB4 to counteract physiological endoplasmic reticulum stress and maintain function by avoiding UPR-mediated dysfunction.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mennerich, D., Kellokumpu, S. & Kietzmann, T. Hypoxia and reactive oxygen species as modulators of endoplasmic reticulum and Golgi homeostasis. Antioxid. Redox Signal. 30, 113–137 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Oberholtzer, N. et al. H2S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response. Sci. Adv. 10, eadp1152 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson, C. et al. The Golgi apparatus: an organelle with multiple complex functions. Biochem. J. 433, 1–9 (2011).

    Article  CAS  PubMed  Google Scholar 

  • Hong, Y. et al. ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors. Nat. Immunol. 24, 1007–1019 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uslu, U. et al. The STING agonist IMSA101 enhances chimeric antigen receptor T cell function by inducing IL-18 secretion. Nat. Commun. 15, 3933 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu, N. et al. STING agonist promotes CAR T cell trafficking and persistence in breast cancer. J. Exp. Med. 218, e20200844 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Wang, X. et al. DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity. Embo J. 42, e110597 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richter, F., Paget, C. & Apetoh, L. STING-driven activation of T cells: relevance for the adoptive cell therapy of cancer. Cell Stress. 7, 95–104 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, W. et al. cGAS-STING-mediated DNA sensing maintains CD8+ T cell stemness and promotes antitumor T cell therapy. Sci. Transl. Med. 12, eaay9013 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Motedayen Aval, L., Pease, J. E., Sharma, R. & Pinato, D. J. Challenges and opportunities in the clinical development of STING agonists for cancer immunotherapy. J. Clin. Med. 9, 3323 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  • Fang, R. et al. Golgi apparatus-synthesized sulfated glycosaminoglycans mediate polymerization and activation of the cGAMP sensor STING. Immunity 54, 962–975.e8 (2021). The study identifies sulfated glycosaminoglycans as being essential for the translocation of STING from the endoplasmic reticulum to the Golgi apparatus and for modulating its activation.

    Article  CAS  PubMed  Google Scholar 

  • Mindell, J. A. Lysosomal acidification mechanisms. Annu. Rev. Physiol. 74, 69–86 (2012).

    Article  CAS  PubMed  Google Scholar 

  • Palmer, D. C. et al. Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. J. Exp. Med. 212, 2095–2113 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin, J. et al. CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging. Nat. Aging 3, 600–616 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eskelinen, E.-L. Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol. Asp. Med. 27, 495–502 (2006).

    Article  CAS  Google Scholar 

  • Zhang, J. et al. Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel. Mol. Cell 83, 2524–2539.e7 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu, J. et al. The OX40-TRAF6 axis promotes CTLA-4 degradation to augment antitumor CD8+ T-cell immunity. Cell. Mol. Immunol. 20, 1445–1456 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Isaaz, S., Baetz, K., Olsen, K., Podack, E. & Griffiths, G. M. Serial killing by cytotoxic T lymphocytes: T cell receptor triggers degranulation, re-filling of the lytic granules and secretion of lytic proteins via a non-granule pathway. Eur. J. Immunol. 25, 1071–1079 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Chang, H.-F. et al. Identification of distinct cytotoxic granules as the origin of supramolecular attack particles in T lymphocytes. Nat. Commun. 13, 1029 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sancak, Y. et al. Ragulator-rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roczniak-Ferguson, A. et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5, ra42 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  • Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ham, H. et al. Lysosomal NKG7 restrains mTORC1 activity to promote CD8+ T cell durability and tumor control. Nat. Commun. 16, 1628 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin, J. et al. Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals. Sci. Immunol. 6, eabg0791 (2021). This work uncovers how ageing reshapes mTORC1 compartmentalization, altering its association with lysosomes and endosomes to influence T cell differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di Cara, F., Savary, S., Kovacs, W. J., Kim, P. & Rachubinski, R. A. The peroxisome: an up-and-coming organelle in immunometabolism. Trends Cell Biol. 33, 70–86 (2023).

    Article  PubMed  Google Scholar 

  • Gilkrist, K. W., Opitz, J. M., Gilbert, E. F., Tsang, W. & Miller, P. Letter: immunodeficiency in the cerebro-hepato-renal syndrome of Zellweger. Lancet 1, 164–165 (1974).

    Article  CAS  PubMed  Google Scholar 

  • Muri, J., Corak, B., Matsushita, M., Baes, M. & Kopf, M. Peroxisomes are critical for the development and maintenance of B1 and marginal zone B cells but dispensable for follicular B cells and T cells. J. Immunol. 208, 839–850 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Vicente-Manzanares, M. & Sánchez-Madrid, F. Role of the cytoskeleton during leukocyte responses. Nat. Rev. Immunol. 4, 110–122 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Martín-Cófreces, N. B., Baixauli, F. & Sánchez-Madrid, F. Immune synapse: conductor of orchestrated organelle movement. Trends Cell Biol. 24, 61–72 (2014).

    Article  PubMed  Google Scholar 

  • Quintana, A. et al. T cell activation requires mitochondrial translocation to the immunological synapse. Proc. Natl Acad. Sci. Usa. 104, 14418–14423 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butte, M. J., Stein, J. V. & Delon, J. The cytoskeleton in T cell migration and activation. Front. Immunol. 13, 1057533 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang, N., Butler, J. P. & Ingber, D. E. Mechanotransduction across the cell surface and through the cytoskeleton. Science 260, 1124–1127 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Shen, C. et al. A Dock8-dependent mechanosensitive central actin pool maintains T cell shape and protects the nucleus during migration. Sci. Immunol. 10, eadt9239 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Douanne, T. & Griffiths, G. M. Cytoskeletal control of the secretory immune synapse. Curr. Opin. Cell Biol. 71, 87–94 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Hammer, J. A., Wang, J. C., Saeed, M. & Pedrosa, A. T. Origin, organization, dynamics, and function of actin and actomyosin networks at the T cell immunological synapse. Annu. Rev. Immunol. 37, 201–224 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Thauland, T. J., Hu, K. H., Bruce, M. A. & Butte, M. J. Cytoskeletal adaptivity regulates T cell receptor signaling. Sci. Signal. 10, eaah3737 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  • Kumari, S. et al. Cytoskeletal tension actively sustains the migratory T-cell synaptic contact. EMBO J. 39, e102783 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basu, R. et al. Cytotoxic T cells use mechanical force to potentiate target cell killing. Cell 165, 100–110 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tello-Lafoz, M. et al. Cytotoxic lymphocytes target characteristic biophysical vulnerabilities in cancer. Immunity 54, 1037–1054.e7 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hwang, S.-M. et al. Transgelin 2 guards T cell lipid metabolism and antitumour function. Nature 635, 1010–1018 (2024).

    Article  PubMed  Google Scholar 

  • Combs, J. et al. Recruitment of dynein to the Jurkat immunological synapse. Proc. Natl Acad. Sci. USA 103, 14883–14888 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hooikaas, P. J. et al. Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells. eLife 9, e62876 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scorrano, L. et al. Coming together to define membrane contact sites. Nat. Commun. 10, 1287 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Voeltz, G. K., Sawyer, E. M., Hajnóczky, G. & Prinz, W. A. Making the connection: how membrane contact sites have changed our view of organelle biology. Cell 187, 257–270 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eisenberg-Bord, M., Shai, N., Schuldiner, M. & Bohnert, M. A tether is a tether is a tether: tethering at membrane contact sites. Dev. Cell 39, 395–409 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Wong, Y. C., Ysselstein, D. & Krainc, D. Mitochondria–lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature 554, 382–386 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hein, M. Y. et al. Global organelle profiling reveals subcellular localization and remodeling at proteome scale. Cell 188, 1137–1155.e20 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Booth, D. M., Várnai, P., Joseph, S. K. & Hajnóczky, G. Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER. Mol. Cell 81, 3866–3876.e3862 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DiGiovanni, L. F. et al. ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox. Science 389, 157–162 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Wang, J. et al. Targeting membrane contact sites to mediate lipid dynamics: innovative cancer therapies. Cell Commun. Signal. 23, 89 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  • Martinvalet, D. The role of the mitochondria and the endoplasmic reticulum contact sites in the development of the immune responses. Cell Death Dis. 9, 336 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • Bantug, G. R. et al. Mitochondria-endoplasmic reticulum contact sites function as immunometabolic hubs that orchestrate the rapid recall response of memory CD8+ T cells. Immunity 48, 542–555.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211.e10 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013.e20 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, Y. et al. Characteristics of premanufacture CD8+ T cells determine CAR-T efficacy in patients with diffuse large B-cell lymphoma. Signal. Transduct. Target. Ther. 8, 409 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sukumar, M. et al. Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab. 23, 63–76 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Si, X. et al. Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation. Cell Metab. 36, 176–192.e10 (2024). A mitochondria-focused compound screening that identifies IDH2 as an enasidenib-targetable checkpoint; IDH2 limits T cell memory by suppressing antioxidant metabolism and histone acetylation.

    Article  CAS  PubMed  Google Scholar 

  • Jaccard, A. et al. Reductive carboxylation epigenetically instructs T cell differentiation. Nature 621, 849–856 (2023).

    Article  CAS  PubMed  Google Scholar 

  • Wenes, M. et al. The mitochondrial pyruvate carrier regulates memory T-cell differentiation and antitumor function. Cell Metab. 34, 731–746.e9 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wenes, M. et al. A novel mitochondrial pyruvate carrier inhibitor drives stem cell-like memory CAR T cell generation and enhances antitumor efficacy. Mol. Ther. Oncol. 32, 200897 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  • Hermans, D. et al. Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity. Proc. Natl Acad. Sci. USA 117, 6047–6055 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frisch, A. T. et al. Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy. Cell Metab. 37, 870–885.e8 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Galluzzi, L., Guilbaud, E. & Garg, A. D. Mitochondrial succinate feeds T cell exhaustion in cancer. Cancer Cell 43, 168–170 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Funk, C. R. et al. PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity. Blood 139, 523–537 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pilipow, K. et al. Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity. JCI Insight 3, e122299 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • Gollapudi, S. & Gupta, S. Reversal of oxidative stress-induced apoptosis in T and B lymphocytes by Coenzyme Q10 (CoQ10). Am. J. Clin. Exp. Immunol. 5, 41 (2016).

    PubMed  PubMed Central  Google Scholar 

  • Finisguerra, V. et al. Metformin improves cancer immunotherapy by directly rescuing tumor-infiltrating CD8 T lymphocytes from hypoxia-induced immunosuppression. J. Immunother. Cancer 11, e005719 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  • Watson, M. J. et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591, 645–651 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma, J. et al. Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria. Nat. Immunol. 25, 552–561 (2024). This study provides deep mechanistic insights into how lithium carbonate modulates lysosomal function to counteract lactic acid-induced immunosuppression in the TME, making lactate available to CD8+T cells as an alternative energy source.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dong, W. et al. D-mannose targets PD-1 to lysosomal degradation and enhances T cell-mediated anti-tumor immunity. Cancer Lett. 591, 216883 (2024).

    Article  CAS  PubMed  Google Scholar 

  • Li, W. et al. Chimeric antigen receptor designed to prevent ubiquitination and downregulation showed durable antitumor efficacy. Immunity 53, 456–470.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Wang, H. et al. Tonic ubiquitylation controls T-cell receptor: CD3 complex expression during T-cell development. EMBO J. 29, 1285–1298 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katoh, Y. et al. Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating β-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody. J. Immunother. Cancer 10, e004616 (2022). The study reveals a novel pharmacological approach to alleviate endoplasmic reticulum stress in T cells by inhibiting SCD1, thereby enhancing their antitumour efficacy.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hurst, K. E. et al. Endoplasmic reticulum stress contributes to mitochondrial exhaustion of CD8+ T cells. Cancer Immunol. Res. 7, 476–486 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tabdanov, E. D. et al. Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments. Nat. Commun. 12, 2815 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • von Heijne, G. Mitochondrial targeting sequences may form amphiphilic helices. EMBO J. 5, 1335–1342 (1986).

    Article  Google Scholar 

  • Braulke, T. & Bonifacino, J. S. Sorting of lysosomal proteins. Biochim. Biophys. Acta Mol. Cell Res. 1793, 605–614 (2009).

    Article  CAS  Google Scholar 

  • Gould, S. J., Keller, G.-A., Hosken, N., Wilkinson, J. & Subramani, S. A conserved tripeptide sorts proteins to peroxisomes. J. Cell Biol. 108, 1657–1664 (1989).

    Article  CAS  PubMed  Google Scholar 

  • Griffiths, G. et al. Localization of the Lys, Asp, Glu, Leu tetrapeptide receptor to the Golgi complex and the intermediate compartment in mammalian cells. J. Cell Biol. 127, 1557–1574 (1994).

    Article  CAS  PubMed  Google Scholar 

  • Navarro, A. P. & Cheeseman, I. M. Identification of a Golgi-localized peptide reveals a minimal Golgi-targeting motif. Mol. Biol. Cell. 33, ar110 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang, J., Griffin, A., Qiang, Z. & Ren, J. Organelle-targeted therapies: a comprehensive review on system design for enabling precision oncology. Signal. Transduct. Target. Ther. 7, 379 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang, Y. C. et al. Cell-penetrating artificial mitochondria-targeting peptide-conjugated metallothionein 1A alleviates mitochondrial damage in Parkinson’s disease models. Exp. Mol. Med. 50, 1–13 (2018).

    PubMed  Google Scholar 

  • Yu, H. et al. Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber’s hereditary optic neuropathy in a mouse model. Proc. Natl Acad. Sci. USA 109, E1238–E1247 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chuah, J.-A., Matsugami, A., Hayashi, F. & Numata, K. Self-assembled peptide-based system for mitochondrial-targeted gene delivery: functional and structural insights. Biomacromolecules 17, 3547–3557 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Fu, Y. et al. Engineering mtDNA deletions by reconstituting end joining in human mitochondria. Cell 188, 2778–2793.e21 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Escrig-Larena, J. I., Delgado-Pulido, S. & Mittelbrunn, M. Mitochondria during T cell aging. Semin. Immunol. 69, 101808 (2023).

    Article  CAS  PubMed  Google Scholar 

  • Das, R. K., O’Connor, R. S., Grupp, S. A. & Barrett, D. M. Lingering effects of chemotherapy on mature T cells impair proliferation. Blood Adv. 4, 4653–4664 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kam, W. W. & Banati, R. B. Effects of ionizing radiation on mitochondria. Free Radic. Biol. Med. 65, 607–619 (2013).

    Article  CAS  PubMed  Google Scholar 

  • Zhao, Q. et al. Target reprogramming lysosomes of CD8+ T cells by a mineralized metal-organic framework for cancer immunotherapy. Adv. Mater. 33, e2100616 (2021).

    Article  PubMed  Google Scholar 

  • Sheikh, F. G., Pahan, K., Khan, M., Barbosa, E. & Singh, I. Abnormality in catalase import into peroxisomes leads to severe neurological disorder. Proc. Natl Acad. Sci. USA 95, 2961–2966 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhattacharyya, S. & Saha, J. Tumour, oxidative stress and host T cell response: cementing the dominance. Scand. J. Immunol. 82, 477–488 (2015).

    Article  CAS  PubMed  Google Scholar 

  • Shah, R., Ibis, B., Kashyap, M. & Boussiotis, V. A. The role of ROS in tumor infiltrating immune cells and cancer immunotherapy. Metab. Clin. Exp. 151, 155747 (2024).

    Article  CAS  PubMed  Google Scholar 

  • Shi, Y. et al. A vaccination with boosted cross presentation by ER-targeted antigen delivery for anti-tumor immunotherapy. Adv. Healthc. Mater. 10, e2001934 (2021).

    Article  PubMed  Google Scholar 

  • Huang, Y. et al. The involvement of the mitochondrial membrane in drug delivery. Acta Biomater. 176, 28–50 (2024).

    Article  CAS  PubMed  Google Scholar 

  • Malhotra, J. D. & Kaufman, R. J. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid. Redox Signal. 9, 2277–2294 (2007).

    Article  CAS  PubMed  Google Scholar 

  • He, X., Li, J., An, S. & Jiang, C. pH-sensitive drug-delivery systems for tumor targeting. Ther. Deliv. 4, 1499–1510 (2013).

    Article  CAS  PubMed  Google Scholar 

  • Siska, P. J. et al. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight 2, e93411 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee, J. & Song, C. H. Effect of reactive oxygen species on the endoplasmic reticulum and mitochondria during intracellular pathogen infection of mammalian cells. Antioxidants 10, 872 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao, Y. et al. Pathogen infection-responsive nanoplatform targeting macrophage endoplasmic reticulum for treating life-threatening systemic infection. Nano Res. 15, 6243–6255 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dumauthioz, N. et al. Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity. Cell. Mol. Immunol. 18, 1761–1771 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Lontos, K. et al. Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors. J. Immunother. Cancer 11, e006522 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  • Pretto, S. et al. A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours. Nat. Metab. 7, 508–530 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang, H. et al. In vivo CRISPR screening reveals nutrient signaling processes underpinning CD8+ T cell fate decisions. Cell 184, 1245–1261.e21 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woodsworth, D. J., Dreolini, L., Abraham, L. & Holt, R. A. Targeted cell-to-cell delivery of protein payloads via the granzyme-perforin pathway. Mol. Ther. Methods Clin. Dev. 7, 132–145 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang, B. et al. Designed endocytosis-inducing proteins degrade targets and amplify signals. Nature 638, 796–804 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Piraner, D. I. et al. Engineered receptors for soluble cellular communication and disease sensing. Nature 638, 805–813 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Tavassolifar, M. J., Vodjgani, M., Salehi, Z. & Izad, M. The influence of reactive oxygen species in the immune system and pathogenesis of multiple sclerosis. Autoimmune Dis. 2020, 5793817 (2020).

    PubMed  PubMed Central  Google Scholar 

  • Bai, R. & Cui, J. Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria. Cancer Lett. 564, 216223 (2023).

    Article  CAS  PubMed  Google Scholar 

  • Ali Hosseini Rad, S. M., Poudel, A., Tan, G. M. Y. & McLellan, A. D. Optimisation of Tet-On inducible systems for sleeping beauty-based chimeric antigen receptor (CAR) applications. Sci. Rep. 10, 13125 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morciano, G. et al. Intersection of mitochondrial fission and fusion machinery with apoptotic pathways: role of Mcl-1. Biol. Cell 108, 279–293 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Kim, E. H., Neldner, B., Gui, J., Craig, R. W. & Suresh, M. Mcl-1 regulates effector and memory CD8 T-cell differentiation during acute viral infection. Virology 490, 75–82 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Tripathi, P., Koss, B., Opferman, J. T. & Hildeman, D. A. Mcl-1 antagonizes Bax/Bak to promote effector CD4+ and CD8+ T-cell responses. Cell Death Differ. 20, 998–1007 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chatzispyrou, I. A., Held, N. M., Mouchiroud, L., Auwerx, J. & Houtkooper, R. H. Tetracycline antibiotics impair mitochondrial function and its experimental use confounds research. Cancer Res. 75, 4446–4449 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moullan, N. et al. Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Rep. 10, 1681–1691 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ottina, E. et al. DNA-binding of the Tet-transactivator curtails antigen-induced lymphocyte activation in mice. Nat. Commun. 8, 1028 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  • Schmitt, A., Schulze-Osthoff, K. & Hailfinger, S. Correspondence: T cells are compromised in tetracycline transactivator transgenic mice. Cell Death Differ. 25, 634–636 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • Li, H. S. et al. Multidimensional control of therapeutic human cell function with synthetic gene circuits. Science 378, 1227–1234 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang, L., Pan, S., Wei, X., Xu, X. & Wei, Q. Arming CAR-T cells with cytokines and more: innovations in the fourth-generation CAR-T development. Mol. Ther. 31, 3146–3162 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenshpan, Y. et al. Synthetic promoters to induce immune-effectors into the tumor microenvironment. Commun. Biol. 4, 143 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He, H. et al. Conditioned CAR-T cells by hypoxia-inducible transcription amplification (HiTA) system significantly enhances systemic safety and retains antitumor efficacy. J. Immunother. Cancer 9, e002755 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  • Bacman, S. R., Williams, S. L., Pinto, M., Peralta, S. & Moraes, C. T. Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs. Nat. Med. 19, 1111–1113 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gammage, P. A., Rorbach, J., Vincent, A. I., Rebar, E. J. & Minczuk, M. Mitochondrially targeted ZFNs for selective degradation of pathogenic mitochondrial genomes bearing large-scale deletions or point mutations. EMBO Mol. Med. 6, 458–466 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mok, B. Y. et al. A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing. Nature 583, 631–637 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho, S. I. et al. Targeted A-to-G base editing in human mitochondrial DNA with programmable deaminases. Cell 185, 1764–1776.e12 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Schmiderer, L., Yudovich, D., Oburoglu, L., Hjort, M. & Larsson, J. Site-specific CRISPR-based mitochondrial DNA manipulation is limited by gRNA import. Sci. Rep. 12, 18687 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, X. et al. Precise modelling of mitochondrial diseases using optimized mitoBEs. Nature 639, 735–745 (2025). mtDNA editing had previously been constrained to nuclease-based methods; the studies by Mok et al. (2020), Cho et al. (2022) and Zhang et al. (2025) demonstrate precise, non-destructive base editing as a breakthrough alternative.

    Article  CAS  PubMed  Google Scholar 

  • Spees, J. L., Olson, S. D., Whitney, M. J. & Prockop, D. J. Mitochondrial transfer between cells can rescue aerobic respiration. Proc. Natl Acad. Sci. USA 103, 1283–1288 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borcherding, N. & Brestoff, J. R. The power and potential of mitochondria transfer. Nature 623, 283–291 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berridge, M. V. et al. Horizontal mitochondrial transfer in cancer biology: potential clinical relevance. Cancer Cell 43, 803–807 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Nakai, R. et al. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome. Nat. Metab. 6, 1886–1896 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nicolás-Ávila, J. A. et al. A network of macrophages supports mitochondrial homeostasis in the heart. Cell 183, 94–109.e23 (2020).

    Article  PubMed  Google Scholar 

  • Hoover, G. et al. Nerve-to-cancer transfer of mitochondria during cancer metastasis. Nature 644, 252–262 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saha, T. et al. Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nat. Nanotechnol. 17, 98–106 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Zhang, H. et al. Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution. Cancer Cell 41, 1788–1802.e10 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikeda, H. et al. Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature 638, 225–236 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baldwin, J. G. et al. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy. Cell 187, 6614–6630.e21 (2024). Studies by Ikeda et al. (2025) and Baldwin et al. (2024) highlight the dynamic mitochondrial exchange between T cells and mesenchymal stromal cells or tumour cells, unveiling new therapeutic opportunities to enhance T cell fitness and antitumour immunity.

    Article  CAS  PubMed  Google Scholar 

  • Court, A. C. et al. Survival advantage of native and engineered T cells is acquired by mitochondrial transfer from mesenchymal stem cells. J. Transl. Med. 22, 868 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin, R.-Z. et al. Mitochondrial transfer mediates endothelial cell engraftment through mitophagy. Nature 629, 660–668 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Durose, W. et al. First documentation of cell-to-cell peroxisome transfer in hematopoietic stem and progenitor cells: a method to relieve stress? Blood 140, 1686–1687 (2022).

    Article  Google Scholar 

  • Kumar, S. et al. Programmed exosome fusion for energy generation in living cells. Nat. Catal. 4, 763–774 (2021).

    Article  CAS  Google Scholar 

  • Wang, J. et al. Human neural stem cell-derived artificial organelles to improve oxidative phosphorylation. Nat. Commun. 15, 7855 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oerlemans, R. A., Timmermans, S. B. & van Hest, J. C. Artificial organelles: towards adding or restoring intracellular activity. ChemBioChem 22, 2051–2078 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simmel, F. C. Synthetic organelles. Emerg. Top. Life Sci. 3, 587–595 (2019).

    Article  PubMed  Google Scholar 

  • Van Oppen, L. M. et al. Biodegradable synthetic organelles demonstrate ROS shielding in human-complex-I-deficient fibroblasts. ACS Cent. Sci. 4, 917–928 (2018).

    Article  Google Scholar 

  • Yang, S. et al. Construction of liposome-based extracellular artificial organelles on individual living cells. Angew. Chem. Int. Ed. Engl. 64, e202415823 (2025).

    Article  CAS  PubMed  Google Scholar 

  • Sigmund, F. et al. Bacterial encapsulins as orthogonal compartments for mammalian cell engineering. Nat. Commun. 9, 1990 (2018). This study provides compelling proof-of-concept for a ‘bottom-up’ approach to genetically encode synthetic organelles that can self-assemble within the cell, enabling applications such as molecular imaging and beyond.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kawalekar, O. U. et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44, 380–390 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Ogando, J. et al. PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes. J. Immunother. Cancer 7, 151 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  • Paillon, N. et al. PD-1 inhibits T cell actin remodeling at the immunological synapse independently of its signaling motifs. Sci. Signal. 16, eadh2456 (2023).

    Article  CAS  PubMed  Google Scholar 

  • van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).

    Article  PubMed  Google Scholar 

  • Loschinski, R. et al. IL-21 modulates memory and exhaustion phenotype of T-cells in a fatty acid oxidation-dependent manner. Oncotarget 9, 13125–13138 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo, Y. et al. Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity. Nat. Immunol. 22, 746–756 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monson, K. R. et al. Inherited mitochondrial genetics as a predictor of immune checkpoint inhibition efficacy in melanoma. Nat. Med. 31, 2385–2396 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  • Henning, A. N., Roychoudhuri, R. & Restifo, N. P. Epigenetic control of CD8+ T cell differentiation. Nat. Rev. Immunol. 18, 340–356 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tavakoli, A., Hu, S., Ebrahim, S. & Kachar, B. Hemifusomes and interacting proteolipid nanodroplets mediate multi-vesicular body formation. Nat. Commun. 16, 4609 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heinrich, L. et al. Whole-cell organelle segmentation in volume electron microscopy. Nature 599, 141–146 (2021). This study introduces deep learning models capable of registering 35 organelle classes in microscopy images across diverse resolutions and cell types, with open-source tools made publicly available for broader research use.

    Article  CAS  PubMed  Google Scholar 

  • Lu, C. et al. Diffusion-based deep learning method for augmenting ultrastructural imaging and volume electron microscopy. Nat. Commun. 15, 4677 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alon, S. et al. Expansion sequencing: spatially precise in situ transcriptomics in intact biological systems. Science 371, eaax2656 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Louvel, V. et al. iU-ExM: nanoscopy of organelles and tissues with iterative ultrastructure expansion microscopy. Nat. Commun. 14, 7893 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lemaître, F. et al. Unveiling the molecular architecture of T cells and immune synapses with cryo-expansion microscopy. Preprint at bioRxiv https://doi.org/10.1101/2025.04.15.648816 (2025).

  • Büttner, M. et al. Challenges of using expansion microscopy for super-resolved imaging of cellular organelles. ChemBioChem 22, 686–693 (2021).

    Article  PubMed  Google Scholar 

  • Zimmermann, J. A. et al. Functional multi-organelle units control inflammatory lipid metabolism of macrophages. Nat. Cell Biol. 26, 1261–1273 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valm, A. M. et al. Applying systems-level spectral imaging and analysis to reveal the organelle interactome. Nature 546, 162–167 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lefebvre, A. E. Y. T. et al. Nellie: automated organelle segmentation, tracking and hierarchical feature extraction in 2D/3D live-cell microscopy. Nat. Methods 22, 751–763 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia Romeu, H., Deville, S. & Salvati, A. Time- and space-resolved flow-cytometry of cell organelles to quantify nanoparticle uptake and intracellular trafficking by cells. Small 17, e2100887 (2021).

    Article  PubMed  Google Scholar 

  • Schraivogel, D. et al. High-speed fluorescence image-enabled cell sorting. Science 375, 315–320 (2022). This work redefines live-cell sorting by introducing high-speed subcellular cytometry as a tool for profiling and selecting cells based on organelle morphometry.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song, D. et al. Identification of an endoplasmic reticulum stress-related gene signature to evaluate the immune status and predict the prognosis of hepatocellular carcinoma. Front. Genet. 13, 850200 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang, Y. et al. Characterizing cancer metabolism from bulk and single-cell RNA-seq data using METAFlux. Nat. Commun. 14, 4883 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang, A., Lyu, C. & Zhao, Y. Predicting T cell mitochondria hijacking from tumor single-cell RNA sequencing data with MitoR. Mathematics 13, 673 (2025).

    Article  Google Scholar 

  • Liu, W., He, H. & Chicco, D. Gene signatures for cancer research: a 25-year retrospective and future avenues. PLoS Comput. Biol. 20, e1012512 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caicedo, A. et al. MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Sci. Rep. 5, 9073 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patananan, A. N. et al. Pressure-driven mitochondrial transfer pipeline generates mammalian cells of desired genetic combinations and fates. Cell Rep. 33, 108562 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakano, T., Nakamura, Y., Park, J.-H., Tanaka, M. & Hayakawa, K. Mitochondrial surface coating with artificial lipid membrane improves the transfer efficacy. Commun. Biol. 5, 745 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gäbelein, C. G. et al. Mitochondria transplantation between living cells. PLoS Biol. 20, e3001576 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhong, Z. et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560, 198–203 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikeda, G. et al. Mitochondria-rich extracellular vesicles from autologous stem cell–derived cardiomyocytes restore energetics of ischemic myocardium. J. Am. Coll. Cardiol. 77, 1073–1088 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marcoux, G. et al. Platelet-derived extracellular vesicles convey mitochondrial DAMPs in platelet concentrates and their levels are associated with adverse reactions. Transfusion 59, 2403–2414 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Suh, J. et al. Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis. Cell Metab. 35, 345–360.e7 (2023).

    Article  CAS  PubMed  Google Scholar 

  • Rosina, M. et al. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue. Cell Metab. 34, 533–548.e12 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayakawa, K. et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535, 551–555 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van der Vlist, M. et al. Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain. Neuron 110, 613–626.e9 (2022).

    Article  PubMed  Google Scholar 

  • Peruzzotti-Jametti, L. et al. Neural stem cells traffic functional mitochondria via extracellular vesicles. PLoS Biol. 19, e3001166 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu, S. et al. Extracellular vesicles meet mitochondria: potential roles in regenerative medicine. Pharmacol. Res. 206, 107307 (2024).

    Article  CAS  PubMed  Google Scholar