Endoplasmic reticulum stress in antitumor immunity and immunotherapy resistance: mechanisms and therapeutic implications

Tumor cells utilize various strategies to enable themselves to survive under adverse conditions and to inhibit the development of antitumor immunity. Factors in the tumor microenvironment (TME), e.g., hypoxia, oxidative stress, and nutrient deprivation, can impair the protein-folding ability of the endoplasmic reticulum (ER) and destroy ER homeostasis both in tumor and immune cells, leading to ER stress. This stress is characterized by the accumulation of misfolded or unfolded proteins. Sensing and responding to ER stress is coordinated by the unfolded protein response (UPR), an integrated signaling pathway controlled by three ER stress sensors: inositol-requiring enzyme 1α (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6). In addition to endowing tumor cells with enhanced abilities for tumorigenesis, metastasis, and treatment resistance, aberrant activation of ER stress also impairs antitumor immunity by modulating the phenotype and function of immune cells in the TME. Therapeutic interventions targeting ER stress can achieve direct tumor-killing effects and simultaneously enhance antitumor immune responses. Here we provide a comprehensive overview of the intrinsic and extrinsic mechanisms by which ER stress shapes antitumor immunity and promotes immunotherapy resistance. By understanding these mechanisms, we discuss that ER stress-targeted strategies hold potential to reinvigorate antitumor immunity and improve immunotherapy outcomes. Furthermore, we explore the potential of ER stress as prognostic and predictive biomarkers for cancer immunotherapy. A thorough understanding of how ER stress affects antitumor immunity, as well as how to improve cancer immunotherapy by modulating ER stress is critical for translating these findings into clinical use.