Macrophage Polarization as a Target for Colorectal Cancer Treatment Optimization: A Systematic Review

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with poor survival rates of late-stage disease. While immune checkpoint blockade (ICB) therapy has transformed treatment for mismatch repair-deficient (MMRd)/microsatellite instability-high (MSI-H) tumors, most CRC cases are mismatch repair-proficient (MMRp)/microsatellite-stable (MSS) and derive little to no benefit from current immunotherapy regimens. Tumor-associated macrophages (TAMs) constitute a significant component of the tumor microenvironment (TME) and exhibit a phenotypic gradient between pro-inflammatory (M1-like) and anti-inflammatory, immunosuppressive (M2-like) states. Although their polarization status is increasingly recognized as a key modulator of immunotherapy efficacy in CRC, a comprehensive synthesis of the literature regarding macrophage polarization and its relevance to improving CRC immunotherapy remains lacking. Methods: A systematic literature search was conducted across PubMed, EMBASE, and ScienceDirect from inception to December 2025 using terms encompassing macrophages, immunotherapy, immune checkpoint expression, colorectal cancer, and microsatellite stability status. Title, abstract, and full-text screening were performed independently by multiple authors. Sixty-five studies were included following PRISMA guidelines. The protocol was prospectively registered on PROSPERO (ID: CRD420251244320). Results: Three key themes were identified: (1) macrophage-mediated mechanisms of resistance to ICB, including M2 polarization driven by the PI3Kγ, STAT3, mTOR, and SIRT-1 axes, immunosuppressive cytokine production (IL-10, TGF-β), and altered immune checkpoint ligand expression; (2) macrophage polarization status and associated biomarkers as prognostic indicators of therapeutic response; (3) emerging macrophage-targeted therapeutic strategies in ongoing clinical trials, including CSF1R inhibitors, CD40 agonists, CD47/SIRPα blockade, and STING agonists. Conclusions: TAM polarization is a critical determinant of immunotherapy resistance and patient prognosis in CRC. Macrophage-targeted strategies, particularly M2-to-M1 repolarization approaches used in combination with existing ICB regimens, represent a promising avenue for expanding immunotherapy efficacy beyond MSI-H disease. Further translational research and randomized controlled trials are needed to validate these targets clinically.