Targeting PKMYT1 enhances antitumor immune responses in castration-resistant prostate cancer

Although immunotherapy has been successful in various tumors, its efficacy in castration resistant prostate cancer (CRPC) is minimal, due to reduced presence of intratumoral immune effector cells in CRPC. How CRPC cells escape immune surveillance is not fully defined. Here we demonstrate that PKMYT1 expression is elevated in CRPC cases, which related to low immune infiltration in these patients. Patients with high PKMYT1 expression exhibit low CD8+ T cells signature and resistance to ICB therapy. Targeting PKMYT1 can suppress CRPC progression, accompanied with increased intratumoral CD8+ T cells. Selective PKMYT1 inhibitor, RP-6306, augmented ICB in a manner dependent on CD8+ T cells. PKMYT1 inhibitors alone or in combination with PD-L1 blockade causes CD8+ T cell infiltration and remarkable tumor suppression, which suggests a promising immunotherapeutic approach in CRPC. Mechanically, targeting PKMYT1 activated the cGAS-STING pathway, which increases expression of type I and II interferon response genes and led to upregulation of key immune regulators. These findings highlight a key role of PKMYT1 in CRPC progression and rationalize PKMYT1 as a potential therapeutic target.