Immunogenic cell death (ICD) is a subtype of regulated cell death characterized by the spatiotemporally coordinated emission of damage-associated molecular patterns (DAMPs), such as calreticulin (CALR), ATP, and high-mobility group box-1 (HMGB1), which collectively prime tumor-specific T-cell responses. Autophagy, a lysosome-dependent catabolic process, is increasingly recognized as a key modifier of antitumor immunity and the tumor microenvironment (TME). In preclinical models, autophagy can not only promote ICD by sustaining endoplasmic reticulum (ER) stress, eukaryotic translation initiation factor-2α (eIF2α) phosphorylation, and secretory pathways, but it can also limit ICD by degrading DAMPs, antigenic cargo, and major histocompatibility complex (MHC) molecules. The net outcome is highly context-dependent and determined by the tumor type, the nature and intensity of the stress, and the level at which autophagy is modulated. Herein, we summarize how autophagy affects the three canonical ICD-associated DAMPs, highlight solid-tumor models in which autophagy supports ICD, and contrast them with systems wherein autophagy inhibition is required for immunogenicity. We then focus on hematological malignancies, especially multiple myeloma, where recent reports implicate the autophagy-related protein GABARAP in bortezomib-induced ICD. Finally, we discuss the translational implications, including rational combinations of autophagy modulators with ICD-inducing chemotherapies, targeted drugs, and cellular immunotherapies, and outline the remaining challenges for safely harnessing the autophagy–ICD axis in the clinical setting.
免疫原性细胞死亡（ICD）是一种受调控的细胞死亡亚型，其特征是损伤相关分子模式（DAMPs）的时空协调释放，例如钙网蛋白（CALR）、ATP和高迁移率族蛋白B1（HMGB1）。这些分子共同激发肿瘤特异性T细胞应答。自噬作为一种依赖溶酶体的分解代谢过程，日益被认为是抗肿瘤免疫和肿瘤微环境（TME）的关键调控因子。在临床前模型中，自噬不仅可通过维持内质网（ER）应激、真核翻译起始因子2α（eIF2α）磷酸化及分泌途径来促进ICD，还能通过降解DAMPs、抗原物质和主要组织相容性复合体（MHC）分子来限制ICD。其净效应高度依赖具体情境，并受肿瘤类型、应激性质与强度以及自噬调控水平的影响。本文系统总结了自噬如何影响三种经典ICD相关DAMPs，重点阐述了自噬支持ICD的实体瘤模型，并与那些需要抑制自噬才能产生免疫原性的体系进行对比。随后聚焦于血液系统恶性肿瘤（特别是多发性骨髓瘤），近期研究提示自噬相关蛋白GABARAP参与硼替佐米诱导的ICD。最后，我们讨论其临床转化意义，包括自噬调节剂与ICD诱导化疗、靶向药物及细胞免疫疗法的合理联用方案，并概述在临床中安全利用自噬-ICD轴尚存的挑战。
肿瘤(癌症)患者之家