Multipathway pharmacological interventions targeting liver-derived immune resistance in colorectal cancer liver metastasis.

Immune checkpoint inhibitors provide durable benefit in mismatch repair-deficient colorectal cancer, but most microsatellite-stable tumors remain resistant, particularly in the presence of liver metastases. Immune resistance in colorectal cancer liver metastasis reflects both baseline MSS-CRC mechanisms, including low neoantigenicity, limited T-cell priming and tumor-intrinsic immune exclusion, and liver-specific or liver-amplified mechanisms, including tolerogenic antigen presentation by hepatic resident cells, macrophage-mediated loss of tumor-reactive T cells, and hepatic stromal, vascular and metabolic remodeling. Across early-phase and retrospective studies, responses to checkpoint-based combinations have been observed more often in patients without active liver metastases, but these exploratory subgroup findings do not yet establish independent predictive value or clinical causality. Antiangiogenic agents, multikinase inhibitors, myeloid- and stromal-targeted therapies, innate immune activation, and liver-directed interventions may partially overcome these barriers, but single-pathway strategies have shown limited efficacy. This Mini Review summarizes the mechanisms and clinical evidence of liver-mediated immune resistance and proposes organ-informed, mechanism-matched therapeutic strategies for colorectal cancer liver metastasis.