Martina Troiani

Microbes hijack prostate cancer therapy Androgens such as testosterone and dihydrotestosterone are essential for male reproduction and sexual function. Androgens can also influence the growth of prostate tumor cells, and androgen deprivation therapy (ADT) either by surgical means (castration) or pharmacological approaches (hormone suppression), is the cornerstone of current prostate cancer treatments. Pernigoni et al . found that when the body was deprived of androgens during ADT, the gut microbiome could produce androgens from androgen precursors (see the Perspective by McCulloch and Trinchieri). Gut commensal microbiota in ADT-treated patients or castrated mice produced androgens that were absorbed into the systemic circulation. These microbe-derived androgens appeared to favor the growth of prostate cancer and helped to facilitate development into a castration- or endocrine therapy–resistant state. —PNK

Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy. Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Mcl-1 for their survival. Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2, an established target for senolytic therapy. While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy.

Mitochondrial dysfunction is a hallmark of cellular senescence. Here, we investigated whether senescent cells release mitochondrial (mt)DNA into the extracellular space and its impact on innate immunity. We found that both primary senescent cells and tumor cells undergoing therapy-induced senescence actively released mtDNA into the extracellular environment. mtDNA released by senescent cells was packaged within extracellular vesicles and selectively transferred to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment. Upon uptake, extracellular mtDNA enhanced the immunosuppressive activity of PMN-MDSCs via cGAS-STING-NF-κB signaling, thereby promoting tumor progression. While STING activation directly induced NF-κB signaling, it also activated PKR-like endoplasmic reticulum kinase (PERK), which further amplified NF-κB activity, in PMN-MDSCs. mtDNA release from senescent cells was mediated by voltage-dependent anion channels (VDACs), and pharmacological inhibition of VDAC reduced extracellular mtDNA levels, reversed PMN-MDSC-driven immunosuppression, and enhanced chemotherapy efficacy in prostate cancer mouse models. These findings suggest that targeting mtDNA release could reprogram the immunosuppressive tumor microenvironment, improving therapeutic outcomes for chemotherapy-treated patients.