Metabolic regulation of tumor angiogenesis in colorectal cancer: mechanisms and therapeutic opportunities

Colorectal cancer (CRC) progression is closely linked to abnormal vascular remodeling. Tumor vessels are structurally disorganized and poorly perfused, creating spatially heterogeneous regions of hypoxia and nutrient deprivation. These conditions reshape tumor metabolism by increasing glycolysis, glutamine utilization, and lipid metabolic plasticity. Metabolic changes, in turn, alter endothelial function and the surrounding tumor microenvironment through lactate accumulation, lipid-derived mediators, amino acid metabolism, and extracellular vesicle-mediated signaling. This reciprocal interaction contributes to vascular instability, impaired drug delivery, immune suppression, and treatment resistance. The VEGF pathway remains the principal therapeutic target in CRC angiogenesis. However, the benefits of anti-VEGF agents are often temporary because tumors activate alternative vascular programs and adapt metabolically to reduced blood supply. Hypoxia-induced HIF signaling is central to this response, but resistance also involves enhanced glycolysis, redox adaptation, lipid remodeling, amino acid metabolism, and communication among tumor, endothelial, stromal, and immune cells.In this review, we examine how metabolic reprogramming regulates angiogenesis in CRC and how vascular dysfunction, in turn, shapes tumor metabolism. We focus on endothelial metabolism, the glycolysis-lactate axis, amino acid and lipid metabolism, vitamin- and cofactor-dependent pathways, and exosomal non-coding RNAs. We also discuss how these mechanisms contribute to resistance to anti-angiogenic therapy and assess the rationale for combining vascular and metabolic interventions. A better understanding of this metabolic-vascular interaction may help identify more durable therapeutic strategies for CRC.