Glycolytic cancer-associated fibroblasts orchestrate metabolic remodeling in the tumor microenvironment

Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment and are predominantly classified according to transcriptional identity. However, this framework overlooks an important dimension of CAF biology, metabolic heterogeneity, which remains insufficiently characterized and is not incorporated into current classification systems. In this review, we advance the concept of glycolytic cancer-associated fibroblasts (glyCAFs) as a metabolically defined stromal subset that functions as a central organizer of the tumor ecosystem. Integrating insights from metabolic profiling, transcriptomics, spatial analyses, and emerging therapeutic studies, we outline a model in which glyCAFs coordinate tumor progression through three interconnected mechanisms: metabolic support of oxidative tumor cells via lactate shuttling, suppression of antitumor immunity through extracellular acidification, and spatial organization of the invasive niche through structured stromal barriers. We further discuss evidence from solid tumors supporting the broader relevance of glyCAF-driven metabolic coupling as a conserved feature of tumor biology. Importantly, we highlight targetable vulnerabilities within the glyCAF-tumor axis, including pathways currently under clinical investigation, and consider the potential of glyCAF abundance as a biomarker of therapeutic response, particularly to immune checkpoint blockade. By integrating metabolic state as an orthogonal axis of CAF identity, we suggest a revised framework for tumor stratification and highlight new opportunities to disrupt tumor-stroma co-dependencies through metabolic-immunologic combination therapies.