Targeting MAFB potentiates immune checkpoint inhibitor efficacy by reprogramming tumor-associated macrophages to an M1-like phenotype in colorectal cancer.

Colorectal cancer (CRC) remains largely resistant to immune checkpoint inhibitors (ICIs) due to an immunosuppressive tumor microenvironment (TME) shaped by M2-like tumor-associated macrophages (TAMs). Identifying transcriptional regulators of M2-like TAMs in CRC could provide strategies to overcome ICI resistance by reprogramming the TME. In this study, we analyzed single-cell RNA-seq data from CRC patients to identify transcriptional regulators of M2-like TAMs. Notably, MAFB expression was predominantly detected in M2-like TAMs and was significantly higher in mismatch repair-proficient (pMMR) CRC than in mismatch repair-deficient (dMMR) CRC. Moreover, MAFB expression was inversely correlated with relapse-free survival in colon cancer patients. In macrophages, MAFB was induced by the IL-4-STAT6 and IL-10-STAT3 pathways, which drive M2 polarization, and was suppressed by M1-polarizing signals. Myeloid-specific deletion of Mafb, in combination with ICI treatment, reduced colon cancer growth by enhancing anti-tumor immunity through increased activity of M1-like TAMs, which led to increased infiltration of NK cells and activated cytotoxic T cells within the TME. Mechanistically, MAFB acts as a transcriptional activator directly promoting Il4ra, Il10, and Arg1 mRNA expression, supported by the identification of MAF recognition element (MARE) sites within these loci. Consistently, ectopic expression of IL-4 receptor α in Mafb-deficient macrophages restored M2 phenotypes comparable to those of wild-type macrophages. These data highlight the critical cell-intrinsic role of MAFB in regulating M2-like TAMs and provide the first evidence that targeting MAFB enhances ICI efficacy in CRC by reprogramming TAMs toward an anti-tumorigenic M1-like phenotype.