From molecular mechanisms to clinical practice: advances in the immune microenvironment and translational therapeutics of colorectal cancer liver metastasis

Colorectal cancer (CRC) ranks third in global incidence and second in cancer-related mortality, with the liver constituting the most frequent target organ for metastatic dissemination and distant organ involvement representing the predominant cause of death. Approximately 20–25% of patients present with synchronous hepatic metastases at initial diagnosis or within 3–6 months thereafter, whereas an additional 20–50% develop metachronous hepatic recurrence following curative-intent resection of the primary tumor, thereby positioning colorectal cancer liver metastasis (CRLM) among the most formidable challenges in oncology. With progressive advances in biological insight, the conceptual framework of CRLM has evolved from the classical ‘seed and soil’ hypothesis into an integrative, multi-dimensional paradigm encompassing the epithelial-mesenchymal transition (EMT) of circulating tumor cells (CTCs), immunostromal crosstalk within the tumor microenvironment (TME), the remote regulatory functions of the gut microbiota and its metabolic products, and the contributions of metabolic reprogramming and epigenetic modifications. This review synthesizes recent advances in the molecular pathogenesis of CRLM, including the formation and modulation of the pre-metastatic niche (PMN), the influence of liver-intrinsic immune tolerance on immunotherapeutic responsiveness, the synergistic regulation of core signaling networks, the pathogenic role of the gut microbiota–metabolism–epigenetics axis, and the role of CTCs within the metastatic cascade. From a clinical perspective, we appraise the progress in surgical resection, immune checkpoint inhibitors (ICIs) and their combination strategies, targeted therapies, locoregional interventions, and emerging metabolic–epigenetic therapeutics, with particular emphasis on the clinically challenging disparity in immunotherapy responses between hepatic and pulmonary metastases, a phenomenon largely attributable to organ-specific immune microenvironments. Furthermore, we delineate the limitations of current investigations, noting that much of the mechanistic evidence derives from preclinical models and that organ-specific clinical observations remain predominantly retrospective in nature, and We emphasize that developing precision treatment strategies based on multidimensional molecular profiling and organ-specific therapeutic regimens will constitute a critical research direction for improving the prognosis of patients with CRLM.