Multi-tyrosine kinase inhibitors (MTKIs) have thus far had limited success in the treatment of castration-resistant prostate cancer (CRPC). Here, we report a phase I–cleared orally bioavailable MTKI, ESK981, with a novel autophagy inhibitory property that decreased tumor growth in diverse preclinical models of CRPC. The antitumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated CXCL10 expression through the interferon-γ pathway and promoted functional T cell infiltration, which resulted in enhanced therapeutic response to immune checkpoint blockade. Mechanistically, we identify the lipid kinase PIKfyve as the direct target of ESK981. PIKfyve knockdown recapitulated ESK981’s antitumor activity and enhanced the therapeutic benefit of immune checkpoint blockade. Our study reveals that targeting PIKfyve via ESK981 turns tumors from cold into hot through inhibition of autophagy, which may prime the tumor immune microenvironment in patients with advanced prostate cancer and be an effective treatment strategy alone or in combination with immunotherapies.

迄今为止，多酪氨酸激酶抑制剂 (MTKI) 在治疗去势抵抗性前列腺癌 (CRPC) 方面的成功有限。在这里，我们报告了一种 I 期清除的口服生物可利用的 MTKI，ESK981，它具有一种新的自噬抑制特性，可在多种 CRPC 临床前模型中降低肿瘤生长。ESK981 的抗肿瘤活性在其上调CXCL10的免疫活性肿瘤环境中最大化通过干扰素-γ途径表达并促进功能性T细胞浸润，从而增强对免疫检查点阻断的治疗反应。从机制上讲，我们将脂质激酶 PIKfyve 确定为 ESK981 的直接靶标。PIKfyve 敲低概括了 ESK981 的抗肿瘤活性并增强了免疫检查点阻断的治疗益处。我们的研究表明，通过 ESK981 靶向 PIKfyve 通过抑制自噬将肿瘤从冷变为热，这可能会启动晚期前列腺癌患者的肿瘤免疫微环境，并且是单独或与免疫疗法联合使用的有效治疗策略。