Navigating the Tumor Microenvironment in Colorectal Liver Metastasis: Barriers to Therapy and Emerging Opportunities

Liver metastases from colorectal cancer (CRC) are a primary cause of poor patient prognosis, closely linked to the liver’s unique tumor microenvironment (TME). Compared to primary tumors, research on the TME of liver metastases remains insufficient. This review systematically summarizes recent advances in TME research concerning colorectal liver metastases (CRLM), emphasizing its organ-specific characteristics, pivotal role in tumor progression, and influence on treatment response. We delve into the intricate cellular components of the TME—including tumor-associated macrophages, cancer-associated fibroblasts, and myeloid-derived suppressor cells—and non-cellular constituents such as the extracellular matrix and soluble factors. Furthermore, we explore the multifaceted mechanisms which the TME drives CRLM progression through establishing pre-metastatic niches, facilitating cancer cell colonization, mediating immune evasion, and inducing drug resistance. Additionally, we evaluate therapeutic strategies targeting the TME, including opportunities and challenges in remodeling cellular components, modulating the extracellular matrix, and developing combination therapies. Ultimately, this review aims to provide theoretical foundations and novel insights for developing more effective anti-metastatic therapies, with the goal of improving the prognosis for CRLM patients.