内质网应激反应在肿瘤中双重作用的研究进展

Advances in Research on the Dual Roles of Endoplasmic Reticulum Stress Response in Tumors

摘要: 内质网应激(Endoplasmic Reticulum Stress, ERS)作为细胞应对内环境紊乱的适应性机制，通过未折叠蛋白反应(Unfolded Protein Response, UPR)的IRE1α、PERK、ATF6三条核心通路调控细胞命运，在肿瘤发生发展中呈现双重作用。轻微或适度的ERS可激活UPR通路，通过促进保护性自噬、增强分子伴侣活性等方式，帮助肿瘤细胞适应缺氧、营养匮乏的微环境，进而促进肿瘤增殖、转移并增强耐药性；持续或过度ERS则会启动CHOP、JNK等下游凋亡通路，诱导肿瘤细胞凋亡，同时调控肿瘤免疫微环境，增强抗肿瘤免疫反应。ERS相关分子如GRP78、CHOP、XBP1s等可作为肿瘤诊断、预后评估及疗效预测的潜在生物标志物，靶向ERS通路的抑制剂与诱导剂也为抗肿瘤治疗提供了新方向，与放疗、化疗、免疫治疗等联合应用展现出良好临床前景。目前，ERS相关药物研发仍面临肿瘤特异性不足、肿瘤异质性、联合治疗方案待优化等挑战。未来需进一步解析ERS在不同肿瘤中的分子调控网络，开发高特异性靶向药物，结合个性化医疗制定精准治疗方案，优化联合治疗策略，为攻克肿瘤耐药、改善患者预后提供新的思路与方法。

Abstract: Endoplasmic Reticulum Stress (ERS) serves as an adaptive mechanism by which cells respond to intracellular homeostasis disturbance. It regulates cell fate through three core pathways of the Unfolded Protein Response (UPR), namely IRE1α, PERK, and ATF6, and plays a dual role in tumorigenesis and tumor progression. Mild or moderate ERS activates the UPR pathway, promoting protective autophagy and enhancing chaperone activity to help tumor cells adapt to hypoxic and nutrient-deficient microenvironments, thereby facilitating tumor proliferation, metastasis, and drug resistance. In contrast, sustained or excessive ERS triggers downstream apoptotic pathways such as CHOP and JNK, inducing tumor cell apoptosis, modulating the tumor immune microenvironment, and enhancing anti-tumor immune responses. ERS-related molecules, including GRP78, CHOP, and XBP1s, can act as potential biomarkers for tumor diagnosis, prognosis evaluation, and therapeutic efficacy prediction. Inhibitors and inducers targeting the ERS pathway have provided new strategies for anti-tumor therapy, and their combination with radiotherapy, chemotherapy, immunotherapy, and other treatments has shown promising clinical prospects. At present, the development of ERS-related drugs still faces challenges such as insufficient tumor specificity, tumor heterogeneity, and the need for optimized combination therapeutic regimens. Future research should further elucidate the molecular regulatory networks of ERS in different tumors, develop highly specific targeted drugs, formulate precise treatment strategies combined with personalized medicine, and optimize combination therapy protocols, so as to provide new ideas and methods for overcoming tumor drug resistance and improving patient prognosis.