Peng Chaosheng, Wang Juan, Wang Shu, Zhao Yan, Wang Haoyuan, Wang Yuhao, Ma Yuxuan, Yang Jianjun
Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Cancer Med. 2025 Mar;14(5):e70684. doi: 10.1002/cam4.70684.
The endoplasmic reticulum (ER) serves as a crucial hub for protein synthesis and processing, playing an essential role in maintaining protein homeostasis. Perturbations, such as hypoxia, oxidative stress, inadequate amino acid supply, Ca imbalance, and acidosis, can disrupt cellular equilibrium and result in the accumulation of misfolded/unfolded proteins within the ER lumen. This triggers ER stress. In response to this stress, an unfolded protein response (UPR) is activated as a mechanism to cope with the stress and restore internal balance. The UPR is regulated by three sensors located in the ER: inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). However, the UPR can promote tumor growth in vivo by affecting tumor angiogenesis, cell migration, cell metabolism, and treatment resistance, and has a huge impact on the tumor microenvironment.
We conducted a literature review of scientific papers on the topic of ER stress in the tumor microenvironment.
This review focuses on the inducing factors of ER stress, the mechanism of the UPR signaling pathway induced by ER stress, and the effect of ER stress on the tumor microenvironment and immune-infiltrating cells. Tumors can regulate their evolution by affecting themselves and the tumor microenvironment through endoplasmic reticulum stress. This study reveals the important role of endoplasmic reticulum stress in the occurrence and development of tumors, and provides new ideas and potential therapeutic targets for the precision treatment of tumors. Future studies can further explore the molecular mechanism of ER stress regulating tumor microenvironment and explore its application potential in clinical diagnosis and treatment.
内质网（ER）是蛋白质合成和加工的关键枢纽，在维持蛋白质稳态中发挥着重要作用。诸如缺氧、氧化应激、氨基酸供应不足、钙失衡和酸中毒等干扰因素会破坏细胞平衡，并导致内质网腔内错误折叠/未折叠蛋白质的积累。这会引发内质网应激。作为应对这种应激的一种机制，未折叠蛋白反应（UPR）被激活，以应对应激并恢复内部平衡。UPR由位于内质网的三种传感器调节：肌醇需求酶1（IRE1）、蛋白激酶RNA样内质网激酶（PERK）和激活转录因子6（ATF6）。然而，UPR可通过影响肿瘤血管生成、细胞迁移、细胞代谢和治疗抗性在体内促进肿瘤生长，并对肿瘤微环境产生巨大影响。
我们对有关肿瘤微环境中内质网应激这一主题的科学论文进行了文献综述。
本综述重点关注内质网应激的诱导因素、内质网应激诱导的UPR信号通路的机制，以及内质网应激对肿瘤微环境和免疫浸润细胞的影响。肿瘤可通过内质网应激影响自身和肿瘤微环境来调节其演变。本研究揭示了内质网应激在肿瘤发生发展中的重要作用，并为肿瘤的精准治疗提供了新的思路和潜在的治疗靶点。未来的研究可以进一步探索内质网应激调节肿瘤微环境的分子机制，并探索其在临床诊断和治疗中的应用潜力。
