Parp/Pi3k Inhibitor Combination Therapy Eradicates C-Myc-Driven Murine Prostate Cancers Via Cgas/Sting Pathway Activation Within Tumor-Associated Macrophages.

The majority of metastatic, castrate-resistant prostate cancer (mCRPC) patients are resistant to immune checkpoint blockade (ICB), so therapeutic strategies to enhance immune-responsiveness are urgently needed. Here we performed a co-clinical trial of PARP inhibitor (PARPi) in combination with PD-1 or PDL-1 antibody in genomically unselected mCRPC patients or homologous-recombination proficient murine models, respectively, which demonstrated lack of efficacy. In contrast, PARPi in combination with PI3K inhibitor (PI3Ki), induced tumor regression via macrophage STING-dependent innate immune activation , and enhanced T-cell infiltration/activation in c-myc driven murine prostate cancer models, which was augmented by PD-L1 blockade. mechanistic studies revealed that PARPi-induced DNA double strand break-associated microvesicles released from tumor cells, coupled with PI3Ki-mediated c-GAS de-repression, were both required for macrophage cGAS/STING pathway activation. These data demonstrate that PARPi/PI3Ki combination triggers macrophage STING-mediated anti-cancer innate immunity, which is sufficient to induce tumor regression in ICB-refractory c-myc-driven prostate cancer.