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

Immunotherapy has achieved significant success in treating various cancers, yet its efficacy in castration resistant prostate cancer (CRPC) is minimal, partly due to the lack of intratumoral immune effector cells in CRPC. Understanding the mechanisms of immune evasion and identifying potential therapeutic strategies to activate innate antitumor immunity are crucial for enhancing the response to immunotherapy. Here we demonstrate that PKMYT1, a member of the WEE1 family, is overexpressed in CRPC tissues. Patients with high PKMYT1 expression exhibit low CD8+ T cells infiltration and resistance to immune checkpoint blockade (ICB). Targeting PKMYT1 can suppress CRPC progression, accompanied with increased intratumoral CD8+ T cells. Selective PKMYT1 inhibitor, RP-6306, augments ICB at the presence of CD8+ T cells. PKMYT1 inhibitor alone or in combination with PD-L1 blockade increases infiltration of CD8+ T cell and remarkable tumor suppression in vivo. Mechanically, targeting PKMYT1 activates the cGAS-STING pathway, enhances interferon signaling, and elevates key immune modulators, including CCL5 and CXCL10. These findings highlight a key role of PKMYT1 in CRPC progression and suggest PKMYT1 as a potential therapeutic target in combination with ICB.