PARP inhibitors restore NK cell function via secretory crosstalk with tumor cells in prostate cancer

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 inhibitors (PARPi) have been approved for the treatment of PCa harboring BRCA1/2 mutations. While the survival benefits conferred by 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 restored NK cell functions by promoting cyclophilin A (CypA) secretion from PCa cells, which correlated with improved prognosis in PCa patients from our and public cohorts. Mechanistically, tumor-derived CypA specifically from PCa cells bound to ANXA6 and activated the downstream FPR1 signaling pathway, leading to increased mitochondrial oxidative phosphorylation and NK cell activation. Pharmacological inhibition of CypA blocked FPR1/AKT signaling and diminished 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 prolonged 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.