Liver microenvironment-driven immunosuppressive niche in colorectal cancer liver metastasis and its therapeutic remodeling

Abstract

Colorectal cancer liver metastasis is the most frequent and clinically important pattern of distant spread in colorectal cancer and remains a major determinant of poor prognosis and treatment failure. In the era of immunotherapy, liver metastasis has emerged as an organ-specific barrier to effective antitumor immune responses. Clinical and translational evidence suggests that this pattern of resistance is observed across both MSI-H/dMMR and MSS/pMMR disease contexts, highlighting the liver metastatic microenvironment as a consistent modifier of immunotherapy response. However, the biological mechanisms by which the liver metastatic environment shapes immunotherapy resistance have not been fully integrated, and the extent to which local hepatic immune suppression influences systemic antitumor immunity remains incompletely defined. This review summarizes the liver-specific biological basis of immunotherapy resistance in colorectal cancer liver metastasis, focusing on three interconnected mechanistic layers, including the pre-existing tolerogenic immune niche of the liver, the local immunosuppressive microenvironment established within liver metastases, and the systemic immune suppression associated with the hepatic sink effect. We further discuss therapeutic strategies aimed at enhancing tumor immunogenicity, reprogramming suppressive myeloid and dendritic cells, restoring the function of CD8+ T cells and innate-like effector lymphocytes, remodeling stromal and vascular barriers, and counteracting liver metastasis-driven systemic immune dysfunction. Future clinical and translational studies should prioritize liver-lesion-specific efficacy, paired primary and metastatic tissue analyses, assessment of liver metastatic burden and activity, and integrated immune biomarkers. A shift from a primary-tumor-centered view toward a liver-microenvironment-oriented framework may provide new opportunities to improve immunotherapy outcomes in patients with colorectal cancer liver metastasis.