Androgen blockade primes NLRP3 in macrophages to induce tumor phagocytosis

Immune-based therapies induce a durable remission in a subset of patients across a wide range of malignancies. There is limited efficacy of immunotherapy in metastatic castrate-resistant prostate cancer, manifested by a predominance of immunosuppressive (M2) tumor-associated macrophages (TAM) in the tumor microenvironment (TME). Therefore, therapeutic strategies to overcome TAM-mediated immunosuppression are critically needed in advanced prostate cancer (PC). Here we demonstrate that NLR family pyrin domain containing 3 (NLRP3), an innate immune sensing protein, is highly expressed in TAM from metastatic PC patients treated with standard-of-care androgen deprivation therapy (ADT). Androgen receptor (AR) blockade in TAM upregulates NLRP3 expression, but not inflammasome. Concurrent AR blockade and NLRP3 agonist (BMS-392959) treatment promoted the phagocytosis of cancer cells by M2 TAM. Contrary, BMS-392959 monotherapy was sufficient to enhance phagocytosis of cancer cells in anti-tumor (M1, scarce within TME) TAM, that already had high NLRP3 expression. Critically, combinatorial treatment with ADT and BMS-392959 in a murine model of advanced PC resulted in significant tumor control, with tumor clearance in 55% of mice via TAM phagocytosis. Collectively, our results support the NLRP3 as an AR-regulated macrophage phagocytic checkpoint, inducibly expressed in TAM by ADT and activated by NLRP3 agonist treatment, the combination resulting in TAM-mediated phagocytosis and tumor control. ### Competing Interest Statement The authors have declared no competing interest.