Cancer cells orchestrate an immunosuppressive tumor ecosystem by acquiring host-derived mitochondria, fusing them with their endogenous mitochondrial network to enhance their own biosynthetic capacity through P5CS conformational changes, and subsequently redistributing these hybrid organelles to neighboring immune cells where they reprogram neutrophils, macrophages, and CD4+ T cells into immunosuppressive states while driving CD8+ T cell exhaustion.

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.

HIGHLIGHTS

Tumor cells regulate their ecosystem by redistributing mitochondria

Redistributed mitochondria expand immunosuppressive cells but exhausts CD8+ T cells

Mitochondria fusion within cancer cells, which precedes redistribution, optimizes metabolic output by triggering conformational changes in P5CS

Mitochondria fusion allows cancer cells to incorporate and refurbish seemingly incompetent host-derived mitochondria, improving efficiency in the tumor ecosystem