T淋巴细胞自噬在抗肿瘤免疫治疗中的研究进展

Research Progress of T Lymphocyte Autophagy in Anti-Tumor Immunotherapy

摘要: 自噬作为一种在进化层面高度保守的生理机制，依赖于溶酶体途径对细胞内物质进行降解与循环利用，在维持细胞稳态及响应外界压力刺激方面扮演者不可或缺的角色。在抗肿瘤免疫领域，自噬对T淋巴细胞的调控呈现高度复杂的情境依赖性。一方面，自噬可以通过降解受损细胞器和错误折叠的蛋白聚集体，并提供代谢中间产物，从而为T细胞的生存、增殖及免疫记忆的建立提供重要支持；另一方面，自噬的过度激活也可促进调节性T细胞的免疫抑制功能，甚至在肿瘤微环境的恶劣营养条件下，通过“自噬性饥饿”来损害效应T细胞的功能。本文系统综述自噬调控CD8⁺细胞毒性T细胞、CD4⁺辅助T细胞、调节性T细胞(Treg)及嵌合抗原受体T (CAR-T)细胞命运与功能的最新研究进展，重点探讨自噬在不同T细胞亚群中的差异化作用及其分子机制，并总结靶向自噬联合免疫检查点抑制剂及代谢重编程策略在肿瘤免疫治疗中的临床应用前景。深刻认识T细胞自噬所具备的“双刃剑”双重属性，对于探索能够精准调控自噬活性的创新免疫治疗手段具有关键指导意义。

Abstract: Autophagy, as a highly conserved physiological mechanism at the evolutionary level, relies on the lysosomal pathway to degrade and recycle intracellular substances, playing an indispensable role in maintaining cellular homeostasis and responding to external stress stimuli. In the field of anti-tumor immunity, the regulation of T lymphocytes by autophagy shows a highly complex context-dependent nature. On the one hand, autophagy can provide important support for the survival, proliferation and establishment of immune memory of T cells by degrading damaged organelles and misfolded protein aggregates and providing metabolic intermediates; On the other hand, excessive activation of autophagy can also promote the immunosuppressive function of regulatory T cells. Even under the harsh nutritional conditions of the tumor microenvironment, it can damage the function of effector T cells through “autophagic starvation”. This article systematically reviews the latest research progress on autophagy regulating the fate and function of CD8⁺ cytotoxic T cells, CD4⁺ helper T cells, regulatory T cells (Treg), and chimeric antigen receptor T (CAR-T) cells, with a focus on exploring the differentiated role of autophagy in different T cell subsets and its molecular mechanisms. And summarize the clinical application prospects of targeted autophagy combined with immune checkpoint inhibitors and metabolic reprogramming strategies in tumor immunotherapy. A profound understanding of the “double-edged sword” dual attributes of T-cell autophagy is of crucial guiding significance for exploring innovative immunotherapy methods that can precisely regulate autophagic activity.