Mitochondria redistribution organizes the immunosuppressive tumor ecosystem

  • bioRxiv. 2025 Nov 13:2025.11.11.687895. doi: 10.1101/2025.11.11.687895.
Azusa Terasaki  1 ,  Alexis T Weiner  1 ,  Yuhao Tan  2 ,  Viktoria Szeifert  1 ,  Keshav Bhatnagar  1 ,  Cara C Rada  3 ,  Vishnu Shankar  4 ,  Courtney Kernick  1 ,  Mahnoor Mahmood  5 ,  Lukas Wiggers  1 ,  Viviana R Rodrigues  1 ,  Payam A Gammage  5  6 ,  Theodore Roth  1  7 ,  Jeffrey D Axelrod  1 ,  Edgar Engleman  1  8 ,  Bo Li  2 ,  Derick Okwan-Duodu  1  8
Affiliations
  • 1. Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • 2. The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3. Department of Medicine, Stanford University, Stanford, CA 94305, USA.
  • 4. Department of Immunology Graduate Program, Stanford University, Stanford, CA 94305, USA.
  • 5. CRUK- Scotland Institute, Glasgow, UK.
  • 6. School of Cancer Sciences, University of Glasgow, UK.
  • 7. Arc Institute, Palo Alto, CA, USA.
  • 8. Stanford Cancer Institute, Stanford, CA 94305.
PMID: 41292779 DOI: 10.1101/2025.11.11.687895
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.

Keywords
immunosuppression; metabolism; mitochondria redistribution; tumor microenvironment.
Products