Metabolic crosstalk between extracellular matrix, cancer-associated fibroblasts and tumor cells: drivers of tumor progression and therapeutic resistance.
TL;DR
This review clarifies the metabolic crosstalk mechanisms between ECM, CAFs and tumor cells, providing a theoretical basis for developing combinatorial therapeutic designs integrating metabolism-targeted agents, stroma-directed therapies and immunotherapy to amplify anti-tumor efficacy.
Abstract
The tumor microenvironment (TME) is a critical regulator of cancer progression, with extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) as core components. Metabolic reprogramming is a hallmark of cancer, yet the metabolic crosstalk between ECM, CAFs and tumor cells updates rapidly and remains incompletely understood, and effective therapeutic strategies targeting this axis are lacking. This review summarizes that ECM stiffness and components remodel glucose, lipid, and amino acid metabolism in tumor cells via mechanotransduction and signaling pathways. Meanwhile, metabolic adaptations in turn drive ECM remodeling. In addition, CAFs exhibit high heterogeneity and undergo glycolytic, lipid, and amino acid metabolic reprogramming, providing metabolites to fuel tumor growth and mediate therapeutic resistance. Importantly, this metabolic rewiring profoundly reshapes the tumor immune microenvironment by promoting M2-like tumor-associated macrophage polarization, regulatory T cell expansion, and inhibiting CD8+ T cell mediated anti-tumor responses etc., thereby fostering immune evasion and therapeutic resistance. The reciprocal interactions among ECM, CAFs, metabolic reprogramming, and immunosuppression form a vicious cycle that drives tumor progression, metastasis, and drug resistance. Distinct from prior reviews that independently elaborate ECM mechanometabolism or CAF metabolic reprogramming, this review establishes a unified tripartite conceptual framework termed the ECM-CAF-Tumor Reciprocal Metabolic Cycle, integrating mechanical, metabolic, and immunological dimensions. This review clarifies the metabolic crosstalk mechanisms between ECM, CAFs and tumor cells, providing a theoretical basis for developing combinatorial therapeutic designs integrating metabolism-targeted agents, stroma-directed therapies and immunotherapy to amplify anti-tumor efficacy.