Mitochondrial DNA lineages determine tumor progression through T cell reactive oxygen signaling

Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA-cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, mtDNA^B6 and mtDNA^NZB, where mtDNA^NZB mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, mtDNA^B6 Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas mtDNA^NZB Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the mtDNA^NZB mice exhibited strikingly impaired tumor growth while mtDNA^B6 mice showed Treg-dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of mtDNA^NZB Teff cells increased mitochondrial gene expression while activation of mtDNA^NZB Treg cells impaired mitochondrial gene expression and resulted in mtDNA^NZB Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized mtDNA^NZB Treg function in both transplant and tumor models, indicating a key role for mROS in promoting Treg dysfunction. Anti-PD-L1 therapy did not modulate these effects, indicating that modulation of host mitochondrial function provides an independent approach for enhancing tumor cell destruction.