Nutritional modulation of metabolic signaling within the tumor microenvironment for cancer therapy.

The tumor microenvironment (TME) constitutes a complex ecosystem of cellular and non-cellular components. Together, these constituents exert a critical influence on cancer progression. A principal mechanism underlying this influence is metabolic reprogramming, in which tumor cells alter glucose, amino acid, and lipid metabolism to promote growth, survival, and immune evasion. Metabolic adaptation is further regulated by nutrient-sensing pathways, including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and hypoxia-inducible factor (HIF), which often exhibit context-dependent and sometimes opposing functions in tumor and immune cells within the TME. Given this complexity, targeting metabolic vulnerabilities has become a promising therapeutic approach. In this context, nutritional interventions, such as caloric restriction, ketogenic diets, fasting-mimicking diets, protein or amino acid modulation, and lipid metabolism adjustments, aim to deprive tumors of essential nutrients, remodel the immunosuppressive TME, and increase cancer cell sensitivity to chemotherapy, radiotherapy, and immunotherapy. However, the efficacy of these interventions varies according to cancer type, oncogenic drivers, and immune contexture, and there is a risk of impairing anti-tumor immune function. Addressing these challenges will require personalized nutrition strategies that integrate tumor genetics, metabolic profiling, and the gut microbiome, together with technological advances for real-time monitoring. Progress in this area depends on a deeper mechanistic understanding of nutrient-immune interactions and the optimization of combination approaches for improved metabolic targeting in precision oncology. Accordingly, this review addresses a critical gap by synthesizing mechanistic and translational literature and outlining actionable priorities to advance nutritional modulation from preclinical research to clinical application.