Panda Sameer Kumar, Sanchez-Pajares Ibone Rubio, Rehman Ayesha, Del Vecchio Vitale, Mele Luigi, Chipurupalli Sandhya, Robinson Nirmal, Desiderio Vincenzo
Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, 80138, Italy.
Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5001, Australia.
Cell Commun Signal. 2025 May 13;23(1):223. doi: 10.1186/s12964-025-02232-w.
Cancer is influenced by the tumor microenvironment (TME), which includes factors such as pH, hypoxia, immune cells, and blood vessels. These factors affect cancer cell growth and behavior. The tumor microenvironment triggers adaptive responses such as endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and autophagy, posing a challenge to cancer treatment. The UPR aims to restore ER homeostasis by involving key regulators inositol-requiring enzyme-1(IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Additionally, ER-phagy, a selective form of autophagy, eliminates ER components under stress conditions. Understanding the interplay between hypoxia, ER stress, UPR, and autophagy in the tumor microenvironment is crucial for developing effective cancer therapies to overcome drug resistance. Targeting the components of the UPR and modulating ER-phagy could potentially improve the efficacy of existing cancer therapies. Future research should define the conditions under which ER stress responses and ER-phagy act as pro-survival versus pro-death mechanisms and develop precise methods to quantify ER-phagic flux in tumor cells.
癌症受肿瘤微环境（TME）影响，肿瘤微环境包括诸如pH值、缺氧、免疫细胞和血管等因素。这些因素会影响癌细胞的生长和行为。肿瘤微环境会引发诸如内质网（ER）应激、未折叠蛋白反应（UPR）和自噬等适应性反应，这对癌症治疗构成了挑战。未折叠蛋白反应旨在通过涉及关键调节因子肌醇需求酶1（IRE1）、PKR样内质网激酶（PERK）和激活转录因子6（ATF6）来恢复内质网的稳态。此外，内质网自噬作为一种选择性自噬形式，可在应激条件下清除内质网成分。了解肿瘤微环境中缺氧、内质网应激、未折叠蛋白反应和自噬之间的相互作用对于开发有效的癌症治疗方法以克服耐药性至关重要。靶向未折叠蛋白反应的成分并调节内质网自噬可能会提高现有癌症治疗的疗效。未来的研究应确定内质网应激反应和内质网自噬作为促生存与促死亡机制起作用的条件，并开发精确方法来量化肿瘤细胞中的内质网自噬通量。
