Mitochondrial genetics defines anti-tumour immunity through mitochondrial ROS and PD-1 signalling

Prota, G.; Justo-Mendez, R.; Gileadi, U.; De Andres-Laguillo, M.; Cabrera-Alarcon, J. L.; Munoz-Hernandez, M. d. M.; Khouili, S. C.; Martinez-De-Mena, R.; Pellico, J.; Benedito, R.; Ruiz-Cabello, J.; Sancho, D.; Enriquez, J. A.; Lechuga-Vieco, A. V.

doi:10.64898/2025.12.07.691020

bioRxiv · 10.64898/2025.12.07.691020

Mitochondrial genetics defines anti-tumour immunity through mitochondrial ROS and PD-1 signalling

Prota, G.·Justo-Mendez, R.·Gileadi, U.·De Andres-Laguillo, M.·Cabrera-Alarcon, J. L.·Munoz-Hernandez, M. d. M.·Khouili, S. C.·Martinez-De-Mena, R.·Pellico, J.·Benedito, R.·Ruiz-Cabello, J.·Sancho, D.·Enriquez, J. A.·Lechuga-Vieco, A. V.

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Abstract

As central players in cell metabolism, mitochondria influence numerous aspects of health and disease, including the initiation and progression of cancer. Although mitochondrial DNA (mtDNA) mutations have been extensively documented in human cancers for decades, the functional impact of mitochondrial haplogroups on tumour biology remains largely unexplored. Here, we investigate the role of mitochondrial variability in tumour biology using conplastic mouse strains, which are animal models with identical nuclear genomes but different mtDNA haplotypes. We showed that the physiologically relevant variation in mitochondrial ROS (mROS) generation, associated with specific clusters of mtDNA single nucleotide polymorphisms (SNPs), modulated immune responses within the tumour microenvironment and altered tumour growth. We observed strain-dependent differences in the abundance of multiple immune subsets and in PD-1 expression in tumour-infiltrating lymphocytes (TILs). In addition, mtDNA haplotypes influenced cancer progression by modulating tumour angiogenesis through an mROS-independent mechanism. These findings connect nucleo-mitochondrial genetic variability to tumour progression, de novo vessel formation and anti-tumour immunity. Tumour immunotherapies should incorporate the spatial and temporal dynamics of cancer evolution and consider mitochondrial genetics as a targetable layer influencing treatment efficacy.

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Prota, G., Justo-Mendez, R., Gileadi, U., De Andres-Laguillo, M., Cabrera-Alarcon, J. L., Munoz-Hernandez, M. d. M., Khouili, S. C., Martinez-De-Mena, R., Pellico, J., Benedito, R., Ruiz-Cabello, J., Sancho, D., Enriquez, J. A., Lechuga-Vieco, A. V.. 2025-12-10. Mitochondrial genetics defines anti-tumour immunity through mitochondrial ROS and PD-1 signalling. https://doi.org/10.64898/2025.12.07.691020

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