The adipose microenvironment in colorectal cancer: Navigating the nexus of inflammation, metabolism, and metastatic reprogramming.

Obesity significantly alters the adipose-tumor microenvironment and enhances colorectal cancer (CRC) progression. Visceral adipose tissue (VAT) becomes metabolically and immunologically activated, driving adipocyte dedifferentiation into cancer-associated adipocytes (CAAs). CAAs secrete adipokines, cytokines, chemokines, and lipid substrates that activate the JAK/STAT3, NF-κB, PI3K/AKT, and HIF-1α pathways in CRC cells, thereby enhancing proliferation, the epithelial-mesenchymal transition (EMT), angiogenesis, and immune escape. Increased fatty acid release and CD36/FABP-mediated uptake further support metabolic rewiring and metastatic potential. Key chemokine axes, CCL2/CCR2, CCL5/CCR5, and CXCL12/CXCR4, coordinate stromal recruitment and organ-specific dissemination, linking VAT inflammation to metastasis. New therapeutic concepts - including inhibition of lipid exchange between adipocytes and tumor, modulation of adipokine and chemokine signaling, and reprogramming of the CAA phenotype - highlight the clinical potential of targeting adipose-mediated tumor progression. In this review, we summarize and systematize the current mechanistic evidence on the interactions between adipose tissue and CRC, highlighting their importance in metastasis and therapy resistance. Despite significant progress, key aspects of adipose tissue modulation of CRC biology remain unexplored, underscoring the need for further mechanistic and translational research.