Mechanism regulation of endoplasmic reticulum stress in multiple myeloma cells: modulation of the UPR, UPS, autophagy, HSPs, and potential therapeutic targets

Multiple myeloma (MM) progression results from complex interactions between tumor cells, cytokines, and the tumor microenvironment (TME). MM cells constantly produce paraprotein, causing endoplasmic reticulum stress (ERS). Cell survival relies on adaptive mechanisms such as the unfolded protein response (UPR), autophagy, and heat shock proteins (HSPs). This review emphasizes the role of ERS in MM cell survival and explores emerging therapeutic strategies targeting ERS-related pathways, including chemical agents, natural compounds, and inhibitors of autophagy, HSPs, or the proteasome. ERS in MM cells is a process that must be understood to provide a more complete understanding of this disease. This review analyzed review articles on ERS in normal cells, cancer, and MM, ERS proteins as drug targets in MM, and reports of scientific papers on ERS and MM. The articles were selected from PubMed from 1998 to 2025. and the Global Cancer Observatory website was also consulted. The primary mechanisms regulating ERS are overexpressed in MM cells, and their inhibition can lead to apoptosis, making them potential therapeutic targets. ERS and autophagy are associated with changes in the immune cells of the TME, acting as an immune-evasive mechanism that promotes malignant progression.

多发性骨髓瘤（Multiple myeloma, MM）的疾病进展源于肿瘤细胞、细胞因子与肿瘤微环境（tumor microenvironment, TME）之间的复杂相互作用。MM细胞持续分泌副蛋白，进而引发内质网应激（endoplasmic reticulum stress, ERS）。细胞存活依赖于未折叠蛋白反应（unfolded protein response, UPR）、自噬及热休克蛋白（heat shock proteins, HSPs）等适应性调控机制。本综述重点阐述了内质网应激在MM细胞存活中的核心作用，并探讨了靶向ERS相关通路的新兴治疗策略，涵盖化学制剂、天然化合物，以及针对自噬、热休克蛋白或蛋白酶体的抑制剂。深入解析MM细胞中的内质网应激过程，可为全面认识该疾病提供关键依据。本综述系统梳理了三类相关文献：聚焦正常细胞、癌症及多发性骨髓瘤内质网应激的综述文章，以ERS蛋白作为MM治疗靶点的相关研究，以及探讨内质网应激与MM关联的科研论文。本次检索的文献来源为1998年至2025年的PubMed数据库，同时参考了国际癌症观察站（Global Cancer Observatory）的公开数据。调控内质网应激的核心通路在MM细胞中呈过表达状态，抑制此类通路可诱导肿瘤细胞凋亡，因此其具备成为潜在治疗靶点的潜力。此外，内质网应激与自噬还与肿瘤微环境内免疫细胞的功能改变密切相关，二者共同构成免疫逃逸机制，进而促进恶性肿瘤的进展。