NAFLD-associated immune remodeling in colorectal cancer liver metastasis: mechanisms and implications for immunotherapy.

Non-alcoholic fatty liver disease (NAFLD) affects over 30% of the global adult population and has been increasingly recognized as an adverse prognostic factor for colorectal cancer (CRC) liver metastasis (CRLM). However, the underlying immune mechanisms remain incompletely understood. This review provides a comprehensive synthesis of how NAFLD-induced lipotoxicity reshapes the hepatic immune microenvironment to create a "fertile soil" for CRC metastatic colonization. We delineate a hierarchical immunosuppressive network involving: (1) lipotoxic apoptosis of CD4+ T cells, depleting the helper T cell pool; (2) expansion and functional reinforcement of regulatory T cells (Tregs) through multiple mechanisms (IL-10/TGF-β/IL-35, CD25-mediated IL-2 competition, CTLA-4 engagement, and granzyme B/perforin production); (3) M2 polarization of tumor-associated macrophages; and (4) recruitment of myeloid-derived suppressor cells (MDSCs) via the CXCL5/CXCR2 axis, which suppress CD8+ T cell function. These processes collectively promote CD8+ T cell exhaustion (marked by PD-1, LAG-3, TIM-3 upregulation) and spatial mismatch with metastatic foci. Importantly, we discuss the emerging evidence linking NAFLD-driven immune dysregulation to reduced responsiveness to immune checkpoint inhibitors, while acknowledging the current limitations in direct clinical validation. By integrating mechanistic insights with therapeutic perspectives, this review offers new targets for risk stratification and combination immunotherapy in the growing NAFLD population. Non-alcoholic fatty liver disease.