Abstract Immune checkpoint inhibitors (ICIs) function by reactivating exhausted T cells in tumor-infiltrating lymphocytes (TILs). Given that mitochondrial dysfunction is a known driver of T cell exhaustion, we sequenced mitochondrial DNA (mtDNA) in TILs and identified mutations in approximately 40% of cases. Many mutations were also identical to those in paired tumor cells, suggesting inter-cellular mitochondrial transfer. In vitro assays confirmed that labeled tumor mitochondria were internalized by TILs, in some cases reaching mutant homoplasmy. The mutant transfer, mediated by extracellular vesicles and tunneling nanotubes, impaired T cell functions. In vivo, such mitochondrial dysfunction compromised anti-PD-1 efficacy and impaired tumor rejection. Clinically, the presence of mtDNA mutations in tumor tissues correlated with shorter survival in ICI-treated patients. Furthermore, tumor-derived mitochondria were also transferred to myeloid cells, including macrophages. While mitochondrial transfer generally promoted macrophage maturation, the transfer of mutant mitochondria induced hypoxia/VEGFA-enriched, glycolysis-biased programs and expanded pro-angiogenic macrophage subsets. Functionally, mutant mitochondrial transfer increased neovascularization and sensitized tumors to anti-angiogenic therapy. These findings reveal tumor-derived mitochondrial transfer as a determinant of immune cell fate, linking organelle genetics to therapeutic vulnerabilities. Citation Format: Yosuke Togashi. Tumor-derived mitochondrial transfer dictates immune cell fate and therapeutic vulnerability abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr SY23-02.
Yosuke Togashi (Fri,) studied this question.