Metabolic crosstalk between cancer and stromal cells: Implications for precision oncology

Metabolic reprogramming is a hallmark of cancer that extends beyond the boundaries of individual tumor cells to encompass a complex metabolic network within the tumor microenvironment (TME). Cancer cells engage in dynamic metabolic crosstalk with stromal components including fibroblasts, immune cells, endothelial cells, and adipocytes through the exchange of metabolites, signaling molecules, and extracellular vesicles. These interactions coordinate energy production, redox homeostasis, and biosynthetic pathways that sustain tumor growth, angiogenesis, immune evasion, and therapeutic resistance. Cancer-associated fibroblasts (CAFs) supply lactate, amino acids, and lipids that fuel tumor anabolism; immune cells undergo metabolic suppression under nutrient competition and acidic stress; endothelial and adipose cells contribute to angiogenesis and metastatic adaptation through glycolysis and lipid transfer. This metabolic dialogue is governed by key signaling pathways (HIF-1α, mTOR, AMPK, c-Myc, PPAR, NRF2) and modulated by epigenetic mechanisms linking metabolic flux to gene expression. Understanding these multilayered communications provides novel insights into the cooperative and competitive nature of tumor metabolism. Emerging technologies such as spatial metabolomics and single-cell multi-omics are now enabling the identification of patient-specific metabolic dependencies. Targeting metabolic symbiosis rather than isolated pathways represents a promising direction for precision oncology, offering opportunities to disrupt tumor stroma cooperation, overcome therapeutic resistance, and personalize metabolism-based interventions.