Lipid metabolic plasticity drives the evolution of tumor resistance: Mechanisms and translational perspectives

Shang Dan; Cao Chenhui; Xu Chuan

doi:10.16689/j.cnki.cn11-9349/r.2026.04.007

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Electronic Journal of Metabolism and Nutrition of Cancer ›› 2026, Vol. 13 ›› Issue (4) : 496-503. DOI: 10.16689/j.cnki.cn11-9349/r.2026.04.007

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Lipid metabolic plasticity drives the evolution of tumor resistance: Mechanisms and translational perspectives

Shang Dan, Cao Chenhui, Xu Chuan

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Abstract

Tumor drug resistance remains one of the most prevalent and clinically challenging causes of treatment failure across chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The role of lipid metabolic reprogramming in driving this resistance has attracted considerable attention in recent years. This review examines the lipid metabolic alterations characteristic of drug-resistant tumor cells, focusing on three interconnected aspects: enhanced exogenous lipid uptake, remodeling of plasma membrane lipid composition, and intracellular lipid droplet accumulation. The molecular mechanisms through which these alterations contribute to resistance against distinct therapeutic modalities are subsequently discussed. Regarding intervention strategies, we analyze existing approaches targeting lipid synthesis enzymes, the cholesterol biosynthetic pathway, antioxidant defense nodes, and rate-limiting steps of fatty acid oxidation, along with their early-stage clinical translation. Given the substantial intratumoral heterogeneity of lipid metabolism and the compensatory limitations inherent to single-target interventions, we propose that future efforts should prioritize integrating single-cell lipidomics with spatial metabolomics to map metabolic vulnerabilities with greater precision, while leveraging emerging technologies such as nano-delivery systems and PROTACs to enhance targeting selectivity and exploring combination strategies built on complementary lethality mechanisms — avenues that hold real promise for overcoming the clinical challenge of drug resistance.

Key words

Lipid metabolism reprogramming / Tumor resistance / Ferroptosis / Lipid droplet compartmentalization / Tumor heterogeneity / Tumor microenvironment / Single-cell lipidomics / Anti-tumor therapy

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Shang Dan, Cao Chenhui, Xu Chuan. Lipid metabolic plasticity drives the evolution of tumor resistance: Mechanisms and translational perspectives[J]. Electronic Journal of Metabolism and Nutrition of Cancer. 2026, 13(4): 496-503 https://doi.org/10.16689/j.cnki.cn11-9349/r.2026.04.007

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