Metabolic crosstalk between extracellular matrix, cancer-associated fibroblasts and tumor cells: drivers of tumor progression and therapeutic resistance.
Aug 2026· International Immunopharmacology· Vol 188, pp.
117308
· 0 citations· 216 references
Medicine
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.
Tumor-associated fibrosis is a pervasive hallmark of solid malignancies that remodels tissue architecture, biochemical signaling, and mechanical properties, thereby profoundly influencing antitumor cellular immunity across cancers. This review summarizes current understanding of the cellular and molecular drivers of fibrotic tumor stroma, highlighting heterogeneous cancer-associated fibroblast (CAF) types (myCAF, iCAF, apCAF), myofibroblasts, vascular cells and infiltrating immune cells. We further discuss the altered extracellular matrix (ECM) landscape characterized by excessive deposition and remodeling of collagens I/III, fibronectin, hyaluronan, proteoglycans, and matrix-regulating enzymes such as LOX and MMPs that collectively define desmoplasia. Particular attention is given to the signaling pathways, epigenetic programs, and metabolic regulators that initiate and sustain fibrogenesis, with the bidirectional crosstalk among tumor cells, CAFs, and immune populations that shapes immune exclusion, dysfunction, and therapeutic resistance. In addition, we review emerging experimental models and spatial multi-omics and single-cell evidence linking stromal states with immune phenotypes across pan-cancer settings. Preclinical and translational studies demonstrate that targeted ECM remodeling, CAF reprogramming, and inhibition of profibrotic signaling pathways can restore immune infiltration and enhance antitumor immunity in a context-dependent manner. This review provides a comprehensive framework for understanding how tumor-associated fibrosis regulates cellular immunity across cancers and offers insights into the development of fibrosis-targeted immunotherapeutic strategies.
Current insights into the molecular mechanisms underlying TME remodeling are summarized, including ECM mechanotransduction, hypoxia-driven signaling, hypoxia-driven signaling, epigenetic regulation, metabolic reprogramming, and extracellular vesicle-mediated communication.
Xiaoying Li, Shuang Dai, Dan Cao et al.· Frontiers in Cell and Develo...· 0 citations
Adipose tissue, once considered a passive fuel store, is now recognized as a dynamic endocrine organ that shapes cancer behavior. Within the tumor microenvironment (TME), cancer-associated adipocytes (CAAs) undergo marked reprogramming—losing large lipid droplets, adopting fibroblast-like features, and intensifying lipolysis—while releasing proinflammatory mediators that accelerate proliferation, invasion, and therapy resistance. This interaction is bidirectional: through cytokines, adipokines, and extracellular vesicles (including exosomal microRNAs), CAAs coordinate immune recruitment, extracellular matrix (ECM) remodeling, and angiogenesis. Mechanistically, several pathways converge at this interface. YAP/TAZ, STAT3, and PI3K/AKT integrate mechanical stress, inflammatory tone, and nutrient cues; metabolic symbiosis—enhanced fatty acid oxidation alongside glycolytic rewiring—supplies energy and redox support. CAAs also amplify metastasis and chemoresistance, particularly in triple-negative breast (TNBC) and pancreatic cancers, via effectors such as CXCL8, FAM3C, and SAA1. Systemic axes also matter in cancer cachexia, adipocyte-derived lipocalin-2 (LCN2) promotes tissue wasting and dampens thermogenesis, while obesity’s chronic inflammation further biases the TME toward tumor promotion. This review synthesizes how CAAs and adipose dynamics drive oncogenesis, progression and therapeutic failure and highlights actionable nodes within the adipose–tumor axis for precision oncology.
Jinmin Shi, S. Abdel-Ghany, Mariam M Abdelfattah et al.· Signal Transduction and Targ...· 0 citations
Breast cancer develops within a metabolically heterogeneous tumor microenvironment characterized by regional hypoxia, glycolytic activation, lactate accumulation, extracellular acidification, and impaired antitumor immunity. Lactate is now recognized not only as a metabolic end product, but also as a transported substrate, a receptor ligand, and a potential source of lysine lactylation.
In this Review, we summarize current evidence on lactate production, MCT1/MCT4-dependent trafficking, GPR81/HCAR1-mediated sensing, immune remodeling, and metabolic–epigenetic regulation in breast cancer. We organize these effects into three interconnected layers. First, extracellular acidification, nutrient competition, and redox stress produce rapid and potentially reversible suppression of CD8⁺ T cells, natural killer cells, and dendritic cells. Second, sustained lactate-rich conditions alter the relative fitness of immune and stromal populations, weakening cytotoxic effectors while supporting regulatory T cells, tumor-associated macrophages, suppressive myeloid populations, and stromal immune exclusion. Third, histone and non-histone lactylation, together with RNA-level and chromatin regulatory mechanisms, may contribute to more durable state fixation. We distinguish direct breast cancer evidence from mechanisms established in other cancers and from transcriptome-based lactylation-associated signatures. We also discuss methodological limitations, subtype-specific evidence, and therapeutic strategies targeting lactate production, transport, sensing, and downstream epigenetic regulation.
Lactate-driven metabolic and epigenetic regulation provides a useful framework for understanding immune evasion and therapeutic resistance in breast cancer. However, direct mechanistic evidence remains concentrated in triple-negative breast cancer and tumor-intrinsic phenotypes. Lactylation should therefore be considered a candidate mechanism of durable state fixation rather than a universal explanation for lactate-associated effects. Future studies integrating direct lactylation measurements, spatial multi-omics, functional perturbation, and patient-derived models will be required to define clinically actionable lactate-dependent states.
Lei Sun, Li Wang, Wanqin Zeng et al.· Clinical Epigenetics· 0 citations
Aberrant extracellular matrix (ECM) remodeling in tumors is characterized by altered deposition, enzymatic cross-linking, degradation, and organization of matrix molecules that in turn can contribute directly to tumor invasiveness, immune evasion, and resistance to therapy. Traditionally, cancer-associated fibroblasts (CAFs) have been considered the principal architects of ECM remodeling in tumors. However, the role of non-fibroblast cell populations in modulating ECM structure and function and how these processes intersect with immune regulation, metabolism, and metastasis is also crucial but currently underappreciated. Challenging the prevailing fibroblast-centric paradigm, this review provides an overview of how non-fibroblast cell types engage in dynamic crosstalk and collectively shape the biochemical and biomechanical landscape of tumors. Therapeutic strategies targeting these alternative stromal players could disrupt pro-tumor ECM dynamics, enhance anti-tumor immunity, and restore tissue homeostasis. Thus, a comprehensive understanding of the intricate network of non-fibroblast stromal cells within the tumor microenvironment (TME) can help elucidate opportunities for precision medicine and personalized cancer care, leading to the development of innovative therapeutic interventions targeting the TME.
Sonal Srivastava, Alyaa Dawoud, Andrew C. Dudley et al.· Cancer Research· 0 citations
This review systematically elaborates on the central role of "tumor-host" metabolic crosstalk in reshaping both the TME and the broader host macroenvironment, suggesting the need for multiscale metabolic interventions to improve cancer treatment efficacy.
Yi Zhang, Caixia Suo, Linchong Sun· Chinese Medical Journal· 0 citations
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