Prostate cancer: new study reveals how senescent cells fuel tumor immunosuppression through mtDNA Release
Institute of Oncology Research
Blocking mtDNA Release Offers a Promising Strategy to Enhance Chemotherapy Efficacy in Prostate Cancer
A recent study led by the Molecular Oncology research group at the Institute of Oncology Research (IOR, affiliated to USI and member of Bios+) has unveiled a novel mechanism by which senescent cells contribute to tumor immune suppression and therapy resistance in prostate cancer.
Cellular senescence, characterized by stable cell cycle arrest and the senescence-associated secretory phenotype (SASP), has long been implicated in cancer development and resistance to therapy. This study expands on previous work by demonstrating that mitochondrial DNA (mtDNA), a critical component of the senescent cell secretome, acts as a potent damage-associated molecular pattern (DAMP). The extracellular mtDNA, by engaging innate immune sensors like cGAS, not only drives local inflammation but also promotes an immunosuppressive milieu that facilitates tumor progression.
Key findings on mtDNA and tumor immunosuppression
Dr. Ping Lai and colleagues from IOR have demonstrated that both primary senescent cells and tumor cells undergoing therapy-induced senescence actively release mtDNA into the extracellular space. Packaged within extracellular vesicles, this mtDNA is preferentially transferred to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment. Once internalized by these cells, the mtDNA is recognized by cGAS and activates both type I interferon and NF-κB signaling pathways. While, the STING-PERK amplifies NF-κB signaling, thereby enhancing the immunosuppressive activity of PMN-MDSCs. This process fuels tumor progression and contributes to resistance against chemotherapy. These insights pave the way for innovative therapeutic strategies that target mtDNA release, potentially enhancing the effectiveness of existing chemotherapy regimens in patients with prostate cancer.
Mechanistic insights and therapeutic implications
The study identifies that mtDNA release is mediated by voltage-dependent anion channels (VDAC). Notably, pharmacological inhibition of VDAC oligomerization using agents such as VBIT-4 significantly reduces extracellular mtDNA levels. This reduction in mtDNA release not only diminishes PMN-MDSC-driven immunosuppression but also restores anti-tumor immunity, enhancing the efficacy of chemotherapy in preclinical prostate cancer models. These findings reveal a critical link between cellular senescence and the immunosuppressive tumor microenvironment. By blocking the release of mtDNA, we can potentially reprogram the immune landscape in prostate cancer, thereby improving therapeutic outcomes for patients.
About the study
To access the full version of the study, please refer to the publication in Immunity. Website: https://www.cell.com/immunity/fulltext/S1074-7613(25)00124-4
