Metabolic reprogramming of cancer associated fibroblasts informs stromal heterogeneity and therapeutic targeting

The tumor microenvironment (TME) refers to the non-malignant cellular and stromal components present within tumors, which play critical roles in cancer initiation, progression, metastasis, and therapeutic response. Among the diverse cellular constituents of the TME, cancer-associated fibroblasts (CAFs) represent a key stromal cell population that is primarily involved in the formation and remodeling of the tumor-associated extracellular matrix (ECM), thereby influencing tumor progression through matrix remodeling, immune modulation, angiogenesis, and metabolic support. In addition, tumor cells undergo metabolic reprogramming to adapt to the hostile conditions of hypoxia and nutrient deprivation within the TME. CAFs may participate in this process by regulating tumor cell metabolism and stromal metabolic crosstalk, thereby contributing to energy supply and biosynthetic support. However, CAFs do not constitute a functionally uniform pro-tumorigenic cell population, as distinct CAF subtypes may exert either tumor-promoting or tumor-suppressive effects depending on tumor type, disease stage, and microenvironmental context. This review aims to systematically summarize the major mechanisms underlying metabolic reprogramming in CAFs, analyze their functional heterogeneity and associated controversies, and further explore targeted therapeutic strategies based on the metabolic characteristics of CAFs.