Metabolic adaptation in colorectal cancer microenvironment: Focus on cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs)

Abstract

Metabolic reprogramming within the tumor microenvironment (TME) is a critical driver of colorectal cancer (CRC) progression, influencing tumor growth, immune evasion, and metastatic dissemination. Cancer-associated fibroblasts (CAFs) undergo adaptive shifts toward aerobic glycolysis, a process often termed the “reverse Warburg effect,” producing high levels of lactate and pyruvate that are shuttled to adjacent CRC cells to fuel oxidative phosphorylation and anabolic biosynthesis. CAFs additionally secrete cytokines and growth factors, including TGF-β, IL-6, and VEGF, which integrate metabolic and signaling networks to stimulate epithelial–mesenchymal transition (EMT), angiogenesis, and metastatic potential. Similarly, tumor-associated macrophages (TAMs) exhibit remarkable metabolic plasticity that correlates with their functional heterogeneity. Beyond the classical M1/M2 dichotomy, TAM subsets display differential reliance on oxidative phosphorylation, fatty acid oxidation, or glycolysis depending on local oxygen and nutrient availability. M2-like TAMs, for example, preferentially use oxidative phosphorylation and fatty acid metabolism to sustain survival in hypoxic niches while secreting immunosuppressive metabolites such as arginase, polyamines, and lactate, which inhibit cytotoxic T-cell function. Crosstalk between CAFs and TAMs amplifies these metabolic adaptations: CAF-derived lactate promotes M2 polarization, while TAMs enhance glycolysis and biosynthetic activity in tumor cells. This study aims to systematically investigate the metabolic reprogramming of CAFs and TAMs within the CRC tumor microenvironment. Specifically, we seek to characterize the metabolic adaptations and heterogeneity of these stromal populations, elucidate their reciprocal interactions with tumor cells, and identify potential metabolic vulnerabilities that can be therapeutically targeted to disrupt tumor growth, immune evasion, and metastatic progression.