Cancer cells undergo profound metabolic reprogramming to meet the high demands of unchecked proliferation within the nutrient-limited tumor microenvironment (TME). While fundamental metabolic pathways are conserved, cancer cells exhibit distinct metabolic fluxes and substrate preferences, meticulously dictated by genetic, epigenetic, and microenvironmental cues that reshape enzyme and transporter profiles. This metabolic rewiring sculpts the TME, fostering both competition and cooperation, often favoring tumor-promoting stromal components (cancer-associated fibroblasts, M2 tumor-associated macrophages), and hinders antitumor immunity. Targeting aberrant cancer metabolism and originating interactions in TME presents a promising therapeutic avenue. However, the inherent metabolic heterogeneity across malignancies necessitates personalized combination therapies and continued research to efficiently target this key cancer hallmark.