脂质代谢重编程驱动肿瘤耐药的演化机制与转化前景

商丹; 曹晨慧; 许川

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

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肿瘤代谢与营养电子杂志 ›› 2026, Vol. 13 ›› Issue (4) : 496-503. DOI: 10.16689/j.cnki.cn11-9349/r.2026.04.007

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脂质代谢重编程驱动肿瘤耐药的演化机制与转化前景

商丹, 曹晨慧, 许川

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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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摘要

肿瘤耐药是常规化疗、靶向治疗与免疫治疗临床失败最常见的原因之一,而近年来脂质代谢重编程在耐药中的作用已被学界高度关注。本文围绕耐药细胞的脂质代谢异常展开讨论,涉及外源脂质摄取增强、细胞膜组成重塑及胞内脂滴蓄积3个方面,并就其参与不同疗法耐受形成的分子机制进行了梳理。干预策略上,重点分析了靶向脂质合成酶、胆固醇合成通路、抗氧化节点及脂肪酸氧化限速步骤的现有方案与早期临床进展。考虑到瘤内脂质代谢异质性较高、单靶点干预易诱发代偿的现实局限,本文认为,将单细胞脂质组学与空间代谢组学结合以定位代谢脆弱点,同时借助纳米递送和蛋白靶向降解嵌合体(PROTAC)等技术提升靶向性、探索联合干预策略,是未来突破耐药瓶颈值得重点关注的方向。

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.

导出引用

商丹, 曹晨慧, 许川. 脂质代谢重编程驱动肿瘤耐药的演化机制与转化前景[J]. 肿瘤代谢与营养电子杂志. 2026, 13(4): 496-503 https://doi.org/10.16689/j.cnki.cn11-9349/r.2026.04.007

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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