Exploring Lipid Metabolic Reprogramming: Mechanistic Insights and Implications for Tumor Radiotherapy

Lipid metabolic reprogramming plays a crucial role in modulating tumor responses to radiotherapy by influencing radiation-induced oxidative damage, membrane repair, ferroptosis, energy stress, and immune regulation. Within the context of ionizing radiation, lipid pathways of particular significance include iron-dependent lipid peroxidation and ferroptosis, cholesterol and phospholipid remodeling that impacts membrane integrity and lipid rafts, lipid droplet-mediated buffering of metabolic stress, fatty acid oxidation-dependent energy supply, and sphingolipid-regulated apoptosis. This review delineates pre-existing tumor lipid programs from IR-induced adaptive responses, highlighting that their contributions to radiosensitivity or radioresistance are contingent upon tumor lineage, genetic background, microenvironmental conditions, and treatment context. The coupling of cancer cells with their microenvironment through lipid interactions, encompassing intercellular lipid transfer, nutrient competition, paracrine lipid mediators, and exosome-mediated signaling, is identified as a central component of radioresistance. In conclusion, therapeutic opportunities are evaluated based on their translational maturity, encompassing a spectrum from mechanistic concepts and preclinical radiosensitization strategies to approaches with emerging clinical significance. This synthesis, focused on radiotherapy, seeks to elucidate how lipid vulnerabilities can be strategically and judiciously exploited to enhance radiation outcomes.