Amino Acid and Lipid Metabolism in Cancer: Mechanisms and Therapeutic Opportunities

Metabolic reprogramming is a defining feature of cancer and a major contributor to immune escape. Beyond the well-defined glycolysis, dysregulated amino acid and lipid metabolism also regulate tumor growth, stress adaptation, and therapeutic resistance. Amino acids such as glutamine, arginine, tryptophan, methionine, serine, and cysteine shape biosynthesis, redox balance, one-carbon metabolism, epigenetic control, and nutrient competition in the tumor microenvironment. Lipid uptake, de novo lipogenesis, fatty acid oxidation, cholesterol remodeling, COX-PGE2 signaling, sphingolipid metabolism, and ferroptosis further influence antigen presentation, immune cell fitness, and checkpoint regulation. However, most studies still consider these metabolic axes separately, leaving the coordinated amino acid-lipid crosstalk across tumor and immune compartments insufficiently defined. This review synthesizes recent advances in amino acid metabolism, including the glutamine axis, arginine-polyamine biology, the tryptophan-kynurenine-AHR pathway, and methionine-dependent methylation programs. It then discusses lipid metabolic programs that regulate dendritic cell cross-presentation, suppressive myeloid polarization, CD8⁺ T cell exhaustion, PD-L1 palmitoylation, MHC-I stability, and lipid-peroxidation-linked ferroptosis. We further integrate nutrient competition, immunometabolic checkpoints, and dual metabolic targeting strategies with immune checkpoint blockade. This review provides a unified framework for identifying metabolic vulnerabilities, designing rational combination therapies and refining precision cancer immunotherapy.