Discovery of a Novel CSF-1R Inhibitor with Highly Improved Pharmacokinetic Profiles and Superior Efficacy in Colorectal Cancer Immunotherapy

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.