Lipid metabolic reprogramming in cancer: bidirectional crosstalk with epigenetic and post-translational regulation in tumor progression and therapeutic adaptation

Lipid metabolic reprogramming is increasingly recognized as a core adaptive feature of cancer, extending well beyond the passive fulfillment of lipid demand during rapid proliferation. By rewiring lipid uptake, de novo lipogenesis, lipid droplet dynamics, fatty acid oxidation, and cholesterol/mevalonate metabolism, tumor cells sustain membrane biogenesis, redox balance, energy production, and survival under hypoxia, nutrient deprivation, oxidative stress, metastatic dissemination, and therapeutic challenge. These adaptations not only support tumor growth and plasticity, but also contribute to immune evasion, tumor microenvironment remodeling, and resistance to anticancer therapies. Lipid metabolic reprogramming can arise from recurrent genomic alterations, oncogenic signaling, microenvironmental stress, and therapeutic pressure. Genetic lesions, oncogenic signaling, epigenetic regulation, and post-translational modifications can act as interacting and sometimes concurrent determinants that initiate, reinforce, redirect, or reversibly adjust lipid-metabolic states. In turn, lipid-metabolic capacity can influence epigenetic and post-translational regulation through the shared nucleo-cytosolic acetyl-CoA pool, whereas fatty acyl-CoA species and mevalonate-derived intermediates provide more direct lipid-derived substrates for protein modification. In this review, we first define the core features of lipid metabolic reprogramming and the functional advantages they confer on cancer cells. We then examine genetic and oncogenic drivers, followed by epigenetic and post-translational mechanisms and the reciprocal feedback through which lipid metabolism reconfigures regulatory programs. We subsequently discuss stress-dependent metabolic adaptation and evaluate therapeutic strategies, clinical translation, biomarker-guided stratification, and rational combination approaches. Lipid metabolic reprogramming represents both a hallmark of tumor adaptation and a potentially actionable therapeutic vulnerability. Defining how genomic lesions, oncogenic signaling, epigenetic regulation, post-translational modifications, and environmental pressures interact to establish, reinforce, and redirect lipid-dependent states may provide a stronger foundation for biomarker-informed patient stratification and precision cancer therapy.