Macrophage reprogramming—rather than depletion—is efficacious in a specific subset of colorectal tumor models

Despite the abundance of macrophages in colorectal cancer (CRC), macrophage-targeted therapy has not demonstrated significant clinical benefit. Here, we show that macrophage populations differ across the consensus molecular subtypes (CMS) of CRC and report the first preclinical study of macrophage targeting using mouse models stratified by CMS class. Whereas pan-macrophage ablation, using a CSF1R-inhibitor, lacked efficacy across CMS classes, genetic deletion of inflammatory chemokine receptors (iCCRs) reprogrammed macrophages towards an anti-tumorigenic phenotype, curtailing tumorigenesis in models of CMS1 CRC. We identify an iCCR-independent anti-tumorigenic antigen-presenting macrophage population necessary for therapeutic efficacy. We further show that individual targeting of the CCR1, CCR2, and CCR5 receptors on CRC macrophages lacks benefit, whereas their combined targeting holds promise. We propose that selective targeting of immunosuppressive macrophage populations, whilst sparing antigen-presenting subsets, should be considered when trialling macrophage-targeted therapies.