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.