Key molecular mechanisms and regulatory networks in colorectal cancer liver metastasis

Colorectal cancer (CRC) continues to show rising incidence and mortality worldwide, with liver metastasis representing the leading cause of death among affected patients. Epidemiological data indicate that approximately 49% of CRC-related deaths are associated with hepatic metastases, and about 25% of patients still develop liver metastasis even after undergoing curative resection. The interplay of various cytokines and immune cells within the tumor microenvironment (TME), along with tumor metabolic reprogramming and gut microbiota, collectively underpins the process of colorectal cancer liver metastasis (CRLM). To date, multiple genes, signaling pathways, and cellular components have been identified as key contributors to the development of CRLM. Although the precise mechanisms driving CRLM remain incompletely understood, emerging evidence suggests that liver metastasis is not restricted to advanced CRC stages and may already be present in a subset of early-stage patients. Based on current evidence, this review proposes that effective anti-metastatic strategies should shift from single-pathway targeting toward integrated interventions that simultaneously regulate the following three dimensions: circulating tumor cells (and their EMT process) as the ‘seeds’, the tumor microenvironment as the ‘soil’, and the gut microbiota and metabolic reprogramming as the ‘environmental modifiers’. This article systematically summarizes the mechanisms and recent advances in the molecular regulatory networks underlying colorectal cancer liver metastasis, with a particular focus on the roles of immune cells and related cytokines in the tumor microenvironment. It aims to provide new insights and potential therapeutic targets for the comprehensive management of this disease and highlights the need to further investigate interactions among these mechanisms, accelerate the development of translational biomarkers, and thereby drive key breakthroughs in the field.