Organ-specific pre-metastatic and metastatic niches in colorectal cancer: “discrepancy in response to immune checkpoint inhibitors in liver and lung metastasis”

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, largely driven by metastatic disease. Increasing evidence suggests that metastasis is dictated by tumor-secreted factors that shape the microenvironment of target organs leading to the formation of the pre-metastatic niche (PMN) and resultant metastatic niche and tumor microenvironment (TME). Tumor-derived factors, including extracellular vesicles, cytokines, and integrins, orchestrate vascular remodeling, immune suppression, and stromal reprogramming in distant organs prior to tumor cell arrival. While many of these processes are shared, the liver develops a highly tolerogenic and immunosuppressive niche characterized by myeloid cell accumulation, T-cell depletion, and systemic immune dampening. In contrast, the lung exhibits a more inflammatory and immune-reactive microenvironment, with enhanced lymphocyte activation but concurrent neutrophil-driven immunosuppression. These differences translate into clinically meaningful disparities in immunotherapy outcomes, with liver metastasis consistently associated with resistance to ICIs, whereas lung metastasis demonstrates relatively improved responses. This review examines the mechanisms underlying PMN formation in CRC, with a particular focus on the liver and lung, and explores how their distinct immune landscapes influence response to immune checkpoint inhibitors (ICIs). It also evaluates the current therapeutic strategies aimed at overcoming organ-specific resistance, including combination immunotherapies, anti-angiogenic agents, targeted therapies, and TME-modulating approaches. Finally, we highlight key limitations in existing evidence and propose future directions, emphasizing the need for organ-specific therapeutic strategies and clinical trial designs. A deeper understanding of PMN biology and organ-dependent immune regulation may enable more effective, tailored treatments for metastatic CRC.