Mitochondria redistribution organizes the immunosuppressive tumor ecosystem

Terasaki, A.; Weiner, A. T.; Tan, Y.; Szeifert, V.; Bhatnagar, K.; Rada, C. C.; Shankar, V.; Kernick, C.; Mahmood, M.; Wiggers, L.; Rodrigues, V. R.; Gammage, P. A.; Roth, T.; Axelrod, J. D.; Engleman, E.; Li, B.; Okwan-Duodu, D.

doi:10.1101/2025.11.11.687895

bioRxiv · 10.1101/2025.11.11.687895

Mitochondria redistribution organizes the immunosuppressive tumor ecosystem

Terasaki, A.·Weiner, A. T.·Tan, Y.·Szeifert, V.·Bhatnagar, K.·Rada, C. C.·Shankar, V.·Kernick, C.·Mahmood, M.·Wiggers, L.·Rodrigues, V. R.·Gammage, P. A.·Roth, T.·Axelrod, J. D.·Engleman, E.·Li, B.·Okwan-Duodu, D.

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Abstract

Hostile conditions in the tumor microenvironment restrict cellular respiration, yet mitochondrial metabolism remains indispensable for tumor growth and the activity of immunosuppressive cells. How tumor ecosystems sustain mitochondrial output has been unclear. Here, we show that cancer cells resolve this paradox by acting as hubs of intercellular mitochondrial redistribution. Using mitochondrial reporter systems, we demonstrate that cancer cells import host-derived mitochondria, integrate them into their endogenous network, and subsequently relay these hybrid organelles to neighboring immune cells. Mitochondria redistribution reprograms recipient neutrophils, macrophages, and CD4+ T cells into highly suppressive states but drives CD8+ T cell exhaustion. Within cancer cells, fusion of incoming mitochondria induces filamentous P5CS assembly, enhances biosynthetic output, and enables the refurbishment of damaged organelles into fully functional units. Disrupting mitochondrial redistribution collapses the immunosuppressive ecosystem and impairs tumor growth. Thus, cancer cells do not hoard resources but orchestrate a redistribution program that fortifies their own metabolic resilience, derails anti-tumor immunity, and sustains immunosuppressive partners. HIGHLIGHTSO_LITumor cells regulate their ecosystem by redistributing mitochondria C_LIO_LIRedistributed mitochondria expand immunosuppressive cells but exhausts CD8+ T cells C_LIO_LIMitochondria fusion within cancer cells, which precedes redistribution, optimizes metabolic output by triggering conformational changes in P5CS C_LIO_LIMitochondria fusion allows cancer cells to incorporate and refurbish seemingly incompetent host-derived mitochondria, improving efficiency in the tumor ecosystem C_LI

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Terasaki, A., Weiner, A. T., Tan, Y., Szeifert, V., Bhatnagar, K., Rada, C. C., Shankar, V., Kernick, C., Mahmood, M., Wiggers, L., Rodrigues, V. R., Gammage, P. A., Roth, T., Axelrod, J. D., Engleman, E., Li, B., Okwan-Duodu, D.. 2025-11-13. Mitochondria redistribution organizes the immunosuppressive tumor ecosystem. https://doi.org/10.1101/2025.11.11.687895

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