Novel therapeutic strategies for targeting fatty acid oxidation in cancer

Metabolic rewiring is a defining feature of malignant cells, enabling them to dynamically exploit nutrient resources to meet bioenergetic problems at different growth stages. Beyond the classical Warburg effect, recent studies have shown that neoplasms demonstrate a marked dependency on lipid metabolism, using free fatty acids to support cellular proliferation and regeneration via fatty acid oxidation (FAO). As a central component of lipid metabolism, FAO exerts dual immunomodulatory functions within tumors. Although numerous studies have described the enzymatic reactions of the FAO pathway in different malignancies, relatively few have investigated the pharmacological disruption of these enzymatic checkpoints and the resulting immunological consequences. Moreover, existing therapeutic strategies have failed to achieve a risk-benefit balance, limiting the clinical translation of FAO-directed approaches. To better understand the therapeutic implications of FAO, we investigated the mechanistic pathways mediated by mitochondrial rate-limiting enzymes, with a particular focus on the carnitine palmitoyltransferase 1 enzyme family-the critical gatekeeper controlling the entry of fatty acids into mitochondrial oxidation instead of CPT2. We comprehensively evaluated its role in tumor biology and also highlight future research directions to inform rational intervention strategies.