《生命科学》 2026, 38(10): 1804-1814
分子伴侣介导的自噬在肿瘤中的研究进展
摘 要：
分子伴侣介导的自噬（chaperone-mediated autophagy， CMA）作为真核细胞内一种高度选择性的自噬途径，通过识别含KFERQ基序的底物蛋白，在维持蛋白质稳态、代谢调控及应激应答中发挥核心作用。CMA在肿瘤发生发展早期阶段抑制肿瘤形成，在进展期则通过促进细胞存活、转移及化疗耐药等机制驱动肿瘤恶性进展。本文综述了CMA的分子机制及其在肿瘤增殖、凋亡、转移、肿瘤微环境互作及耐药中的多维度功能，并重点探讨了以LAMP2A和Hsc70 为靶点的抑制剂研发、联合治疗策略及临床前研究进展，旨在为克服肿瘤治疗耐药和探索肿瘤治疗新靶点提供理论依据和研究方向。
通讯作者：盛德乔 , Email:shengdq@ctgu.edu.cn 杨轶 , Email:yangyi1@ctgu.edu.cn
Abstract:
Chaperone-mediated autophagy (CMA) is a highly selective lysosomal degradation pathway in eukaryotic cells that plays a crucial role in maintaining proteostasis, regulating cellular metabolism, and mediating adaptive responses to stress, primarily through the recognition of substrate proteins bearing the KFERQ-like pentapeptide motif. This article presents a systematic review of the molecular mechanisms underlying CMA and its multifaceted functions in tumor proliferation, apoptosis, metastasis, interaction with the tumor microenvironment, and drug resistance. Furthermore, it emphasizes the development of inhibitors targeting LAMP2A and Hsc70, combined treatment strategies, and the advancements in preclinical research. CMA inhibits tumor formation in the early stages of tumor, but drives malignant progression in advanced stages through promoting cell survival, metastasis, and chemotherapy resistance. The dual functional roles of CMA are governed by a constellation of interdependent molecular mechanisms. Specifically, the activation of the PI3K/AKT signaling pathway facilitates CMA-dependent metabolic reprogramming, primarily through the post-translational modulation of pyruvate kinase M2 (PKM2). In contrast, the regulatory influence of the Wnt/β -catenin pathway on CMA exhibits context-dependent reversibility, contingent upon the mutational status of key components such as APC or β-catenin. At the epigenetic level, CMA modulates transcriptional programs by selectively degrading histone-modifying enzymes, thereby integrating with broader epigenetic regulatory networks to underpin its functional duality. Furthermore, driver gene mutations, including those in TP53 and KRAS, exert distinct, often opposing effects on CMA activity, contributing to its context-specific functional outcomes. This review critically evaluates the evolving therapeutic strategies for modulating CMA. The field has advanced from initial genetic approaches to the development of small-molecule inhibitors, primarily focusing on targeting LAMP2A or its upstream regulators. Rationally designed combination therapies—strategically integrating CMA inhibition with established treatments—have demonstrated improved efficacy in preclinical models of refractory cancers. A central thesis of this review posits that the therapeutic success of CMA-targeted interventions is critically dependent on precise patient stratification, guided by tumor type, genetic background, and disease stage. Moving forward, research efforts should prioritize the identification and validation of robust biomarkers predictive of CMA dependency, as well as the optimization of context-specific combination regimens. A precision medicine framework will be essential to fully realize the therapeutic potential of CMA inhibition, maximizing antitumor effects while minimizing off-target toxicity and translating mechanistic discoveries into meaningful clinical benefits. In summary, this article systematically reviews recent advances in CMA-targeted therapeutic strategies, aiming to provide a theoretical framework and outline future directions for developing novel interventions to overcome resistance to cancer treatment.
Communication Author：SHENG De-Qiao , Email:shengdq@ctgu.edu.cn YANG Yi , Email:yangyi1@ctgu.edu.cn
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