**Background:** Cancer cells face extreme conditions within tumor microenvironments (TMEs), including hypoxia, nutrient starvation, and acidic pH. These conditions drive metabolic adaptations that promote cancer cell malignancy. Originally described by Otto Warburg in the 1950s, cancer cells exhibit altered metabolism compared to normal cells, notably through enhanced glycolysis even in the presence of oxygen (the Warburg effect). This review discusses metabolic adaptations at the cellular, multicellular, and organelle levels within TMEs.
**Methods:** This is a narrative review synthesizing findings from multiple studies, including the authors' own work on multilayered analyses of hypoxia, nutrient starvation, and acidic pH conditions. The authors discuss published data on metabolic pathways, cell-cell interactions, and organelle communication in cancer.
**Key Results:** The review highlights several key findings: (1) Hypoxic TME conditions occur in cell layers approximately 85–100 μm from tumor vessels (oxygen concentration <1%). Under hypoxia, HIF-α subunits stabilize and form heterodimers with HIF-1β, inducing VEGF, angiogenesis, and glycolytic genes such as LDHA and GLUT1. (2) Acidic TME (pH <6.8) results from lactate and proton accumulation due to enhanced glycolysis. Extracellular acidity promotes cytoskeletal remodeling, MMP9 production, and invasive capacity. (3) Under nutrient-deprived conditions, cancer cells switch acetyl-CoA sources from citrate to acetate via the enzyme ACSS2. (4) SREBP2, a cholesterol metabolism regulator, is activated in acidic pH environments. (5) In pancreatic tumors, cancer-associated fibroblasts (CAFs) secrete alanine to support TCA cycle metabolism in cancer cells, and CAF-derived branched-chain amino acids rescue pancreatic cancer cells that rely on branched-chain keto acids. (6) In ovarian cancer, enhanced GLUL expression in CAFs is coupled with enhanced glutaminase in cancer cells, indicating CAF-supported glutamine supply. (7) Increased methionine consumption by cancer cells leads to methionine depletion in cytotoxic T cells, impairing T-cell function. (8) Glucose is not limiting within the TME, but certain amino acids (tryptophan, alanine, arginine, serine, glycine) can be limiting. (9) Organelle communication—including lysosome-mTOR amino acid sensing, mitochondrial dynamics, Golgi-ER fusion, and ER stress responses—plays a central role in metabolic adaptation. The authors report a novel transcriptional regulatory mechanism via Golgi-ER fusion that activates cholesterol biosynthesis in the TME (unpublished data).
**Clinical Implications:** The review suggests that targeting tumor acidity by inhibiting glycolysis or monocarboxylate transporters (MCTs) may boost immune-based cancer therapy. Metabolic adaptations in cancer cells represent new targets for drug discovery, as druggable targets are shifting from cancer cells themselves to TME factors. The authors note that mTOR inhibitors such as rapamycin are not complete cures for cancer, suggesting the existence of adaptive amino acid metabolism independent of mTOR signaling. A better understanding of metabolic adaptations at both single-cell and organelle levels may lead to new therapeutic strategies. Current limitations include the inability to determine whether metabolite signals detected in vivo originate from cancer cells or other cells within the TME, though single-cell resolution metabolic analyses combined with single-cell RNA epigenetic analyses may overcome this.