Blocking CSF-1/CSF-1R pathway has emerged as a promising strategy to remodel tumor immune microenvironment (TME) by reprogramming tumor-associated macrophages (TAMs). In this work, a novel CSF-1R inhibitor C19 with a highly improved pharmacokinetic profile and in vivo anticolorectal cancer (CRC) efficiency was successfully discovered. C19 could effectively reprogram M2-like TAMs to M1 phenotype and reshape the TME by inducing the recruitment of CD8⁺ T cells into tumors and reducing the infiltration of immunosuppressive Tregs/MDSCs. Deeper mechanistic studies revealed that C19 facilitated the infiltration of CD8⁺ T cells by enhancing the secretion of chemokine CXCL9, thus significantly potentiating the anti-CRC efficiency of PD-1 blockade. More importantly, C19 combined with PD-1 mAb could induce durable antitumor immune memory, effectively overcoming the recurrence of CRC. Taken together, our findings suggest that C19 is a promising therapeutic option for sensitizing CRC to anti-PD-1 therapy.

中文翻译：

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发现一种新型 CSF-1R 抑制剂，在结直肠癌免疫治疗中具有显着改善的药代动力学特征和卓越功效

阻断 CSF-1/CSF-1R 通路已成为通过重新编程肿瘤相关巨噬细胞 (TAM) 来重塑肿瘤免疫微环境 (TME) 的有前途的策略。在这项工作中，成功发现了一种新型 CSF-1R 抑制剂C19，其具有显着改善的药代动力学特征和体内抗结直肠癌 (CRC) 功效。C19可以有效地将 M2 样 TAM 重编程为 M1 表型，并通过诱导 CD8 ⁺ T 细胞招募到肿瘤中并减少免疫抑制性 Tregs/MDSC 的浸润来重塑 TME。更深入的机制研究表明，C19通过增强趋化因子 CXCL9 的分泌来促进 CD8 ⁺ T 细胞的浸润，从而显着增强 PD-1 阻断的抗 CRC 效率。更重要的是，C19联合PD-1 mAb可以诱导持久的抗肿瘤免疫记忆，有效克服CRC的复发。综上所述，我们的研究结果表明，C19是一种有前途的治疗选择，可以提高 CRC 对抗 PD-1 疗法的敏感性。