Fuelling resistance: Lipid metabolic rewiring in cancer response to chemotherapy and radiotherapy.

Resistance to chemotherapy and radiotherapy remains a major challenge in cancer treatment and is closely linked to treatment failure and poor patient outcome. While metabolic rewiring is a well-established hallmark of cancer, the specific role of lipid metabolism in promoting therapy resistance has only recently gained attention. Cancer cells modulate lipid metabolic pathways to support survival, maintain redox balance, enable membrane remodelling, enhance DNA repair, and evade cell death under therapeutic stress. They do so by altering fatty acid synthesis, fatty acid oxidation, and lipid storage, ultimately contributing to resistance to genotoxic therapies. These adaptations also intersect with non-apoptotic cell death pathways such as ferroptosis and cuproptosis, and are regulated in part by post-translational modifications including acetylation and lipidation. Moreover, chemotherapy and radiotherapy can further promote metabolic adaptations that increase lipid dependence and reinforce resistant phenotypes. Recognizing these metabolic dependencies has revealed potential molecular targets within lipid metabolism, offering new opportunities to overcome resistance by co-targeting metabolic plasticity alongside standard therapies. Therapeutic strategies that disrupt lipid-driven adaptations may therefore help re-sensitise resistant tumours, enhance therapeutic efficacy, and expand treatment options.