Stress-mediated reactive oxygen species from mitochondria dysregulates the tumor microenvironment in prostate cancer

Prostate cancer (PCa) demonstrates notable disease heterogeneity, with African American men (AAM) experiencing a higher incidence and increased mortality rates compared to their European American (EAM) counterparts. While social determinants of health are key contributors to these differences, underlying biological differences remain important drivers of disease severity and outcomes. In the current work, we aimed to explore the interplay between stress mediated reactive oxygen species and inflammatory signaling in promoting progression of PCa in AAM. The study used a retrospective race-matched Genomic Resource Intelligent Discovery (GRID) database (NCT02609269) ( n = 8,626), and the prospective VANDAAM study (NCT02723734) ( n = 243) to identify hallmarks of oxidative stress and inflammatory signaling in PCa from AAM. We demonstrate that DNA damage repair (DDR) pathway genes are significantly downregulated in AAM-derived PCa, with sustained γH2AX phosphorylation following radiotherapy confirming impaired DNA damage resolution. Transcriptomic analyses further revealed that mitochondrial electron transport chain (ETC) Complex I and Complex III genes are among the most differentially downregulated in AAM, functionally resulting in elevated basal mitochondrial ROS and enhanced sensitivity to ETC inhibition. These mitochondrial ROS-mediated changes promoted lipid peroxidation, plasma membrane remodeling, and extracellular release of ATP and its immunosuppressive metabolite adenosine, selectively in AAM-derived cells and patient-derived explants. Reduced ETC expression further correlated with upregulation of immunosuppressive gene signatures. These findings establish a novel mechanistic framework linking impaired DDR to mitochondrial ETC dysregulation, elevated ROS, and immunosuppressive signature in PCa from AAM, highlighting potential therapeutic targets to address racial disparities in this high-risk population.