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INTERNATIONAL CONGRESS OF

CancerGenetics

• Metabolic Interactions in Cancer: A Contemporary Review of TME Crosstalk and Therapeutic Insights

• Maryam Shirmohamadi,^1,* Javad Fazeli,²
  1. Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
  2. 1Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
  
  
  
• Introduction: Introduction: Cancer is increasingly recognized as a genetic and metabolic disease. Tumour cells reprogram their metabolism to promote survival, proliferation, and resistance to therapy. However, these metabolic adaptations do not occur in isolation. Tumour cells interact metabolically with stromal, immune, and endothelial cells within the tumor microenvironment (TME). These interactions influence tumor progression, evasion of the immune system, and response to treatment. Recent advances in single-cell and spatial metabolomics have provided new insights into these complex relationships.
• Methods: Methods: For this review, peer-reviewed articles published in 2024 and 2025 in the PubMed, Web of Science, and Scopus databases were analyzed. Search terms included: 'cancer metabolism',” 'tumour microenvironment',” 'metabolic crosstalk',” 'spatial metabolomics', and 'immunometabolism'.” Inclusion criteria focused on studies that addressed nutrient competition, metabolic polarization of immune cells, microbiome-derived metabolites, and metabolism-targeted therapies.
• Results: Results Tumor cells reprogram their metabolism to outcompete immune cells for critical nutrients such as glucose, amino acids, and fatty acids, creating a nutrient-deprived microenvironment that impairs immune function. In this setting, stromal cells like tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) engage in metabolic symbiosis by releasing lactate and lipid-derived metabolites that support tumor proliferation and immune suppression. Elevated levels of lactate and kynurenine within the tumor microenvironment (TME) drive metabolic exhaustion of cytotoxic T cells and promote the polarization of TAMs toward an M2-like, tumor-supportive phenotype via regulators such as CPT1A and ACLY. Hypoxic regions within tumors activate HIF-1α, leading to a glycolytic shift and lactic acid accumulation, which in turn acidifies the TME, impairs dendritic cell maturation, and promotes angiogenesis. Spatial and single-cell metabolomic technologies have revealed previously unrecognized metabolic heterogeneity, uncovering distinct metabolic zones and cell-type-specific interactions within tumors. Systemic factors—including obesity, diet, and physical activity—alongside microbiome-derived metabolites such as short-chain fatty acids, further influence tumor metabolism and modulate immune responses and treatment efficacy. Therapeutically, metabolic inhibitors targeting glycolysis (e.g., LDH-A), glutaminolysis (e.g., GLS), and lipid metabolism (e.g., FASN) are being explored in clinical trials, often in combination with immunotherapies, while novel strategies involving engineered probiotics and nanocarriers are under development to reprogram the metabolic landscape of the TME.
• Conclusion: Conclusion: Metabolic interactions within the tumor microenvironment play a central role in cancer progression, evasion of the immune system and treatment resistance. A deeper understanding of these dynamic processes — through technologies such as spatial metabolomics and integrated multi-omics— - may enable precise metabolic therapies. Future strategies must consider the metabolic plasticity of cancer and the heterogeneity of the tumor ecosystem to achieve lasting therapeutic results.
• Keywords: Keywords: Cancer metabolism; Tumor microenvironment (TME); Metabolic crosstalk; Immune cell polariza