Abstract

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the main cause of cancer-related death in men worldwide. Poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for the treatment of PCa harboring BRCA1/2 mutations. While the survival benefits conferred by PARP inhibitors (PARPi) may extend beyond this specific patient population based on evidence from recent clinical trials, the underlying mechanisms remain unexplored. Here, we demonstrate that PARPi substantially restore natural killer (NK) cell functions by promoting cyclophilin A (CypA) secretion from PCa cells, which correlates with improved prognosis in PCa patients from our and public cohorts. Mechanistically, tumor-derived CypA specifically from PCa cells binds to ANXA6 and activates the downstream FPR1 signaling pathway, leading to increased mitochondrial oxidative phosphorylation and NK cell activation. Pharmacological inhibition of CypA blocks the FPR1-AKT signaling and diminishes the cytotoxic effects of NK cells, thereby compromising the therapeutic efficacy of PARPi against PCa. Conversely, combining NK cell adoptive transfer therapy with PARPi markedly prolongs survival in mice bearing PCa. Collectively, we reveal a unique secretory crosstalk between PCa cells and NK cells induced by PARPi and propose a promising strategy for treating PCa.