Discovery of a Novel CSF-1R Inhibitor with Highly Improved Pharmacokinetic Profiles and Superior Efficacy in Colorectal Cancer Immunotherapy
Qi Lv, Hongqiong Yang, Dan Wang, Haikun Zhou, Juan Wang, Juan Wang, Yishu Zhang, Dapeng Wu, Yingbai Xie, Yingshan Lv, Lihong Hu, Junwei Wang, Junwei Wang
Abstract
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.