Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China.
Cell Commun Signal. 2024 Jan 31;22(1):89. doi: 10.1186/s12964-023-01438-0.
The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates the unfolded protein response (UPR). As an adaptive cellular response to hostile microenvironments, such as hypoxia, nutrient deprivation, oxidative stress, and chemotherapeutic drugs, the UPR is activated in diverse cancer types and functions as a dynamic tumour promoter in cancer development; this role of the UPR indicates that regulation of the UPR can be utilized as a target for tumour treatment. T-cell exhaustion mainly refers to effector T cells losing their effector functions and expressing inhibitory receptors, leading to tumour immune evasion and the loss of tumour control. Emerging evidence suggests that the UPR plays a crucial role in T-cell exhaustion, immune evasion, and resistance to immunotherapy. In this review, we summarize the molecular basis of UPR activation, the effect of the UPR on immune evasion, the emerging mechanisms of the UPR in chemotherapy and immunotherapy resistance, and agents that target the UPR for tumour therapeutics. An understanding of the role of the UPR in immune evasion and therapeutic resistance will be helpful to identify new therapeutic modalities for cancer treatment. Video Abstract.
内质网（ER）中未折叠或错误折叠蛋白质的积累会导致 ER 应激，并激活未折叠蛋白反应（UPR）。作为一种对缺氧、营养缺乏、氧化应激和化疗药物等恶劣微环境的适应性细胞反应，UPR 在多种癌症类型中被激活，并在癌症发展中作为一个动态的肿瘤促进因子发挥作用；UPR 的这一作用表明，调节 UPR 可以作为肿瘤治疗的靶点。T 细胞耗竭主要是指效应 T 细胞失去效应功能并表达抑制性受体，导致肿瘤免疫逃逸和肿瘤控制的丧失。新出现的证据表明，UPR 在 T 细胞耗竭、免疫逃逸和对免疫治疗的抵抗中起着关键作用。在这篇综述中，我们总结了 UPR 激活的分子基础、UPR 对免疫逃逸的影响、UPR 在化疗和免疫治疗耐药性中的新机制，以及针对 UPR 的肿瘤治疗药物。了解 UPR 在免疫逃逸和治疗耐药性中的作用将有助于为癌症治疗确定新的治疗模式。视频摘要。
