Cancer cells encounter numerous stresses that pose a threat to their survival. Tumor microenviroment stresses that perturb protein homeostasis can produce endoplasmic reticulum (ER) stress, which can be counterbalanced by triggering the unfolded protein response (UPR) which is considered the canonical ER stress response. The UPR is characterized by three major proteins that lead to specific changes in transcriptional and translational programs in stressed cells. Activation of the UPR can induce apoptosis, but also can induce cytoprotective programs such as autophagy. There is increasing appreciation for the role that UPR-induced autophagy plays in supporting tumorigenesis and cancer therapy resistance. More recently several new pathways that connect cell stresses, components of the UPR and autophagy have been reported, which together can be viewed as non-canonical ER stress responses. Here we review recent findings on the molecular mechanisms by which canonical and non-canonical ER stress responses can activate cytoprotective autophagy and contribute to tumor growth and therapy resistance. Autophagy has been identified as a druggable pathway, however the components of autophagy (ATG genes) have proven difficult to drug. It may be the case that targeting the UPR or non-canonical ER stress programs can more effectively block cytoprotective autophagy to enhance cancer therapy. A deeper understanding of these pathways could provide new therapeutic targets in cancer.

癌细胞遇到许多对其生存构成威胁的压力。肿瘤微环境强调扰乱蛋白质稳态会产生内质网 (ER) 应激，可以通过触发未折叠蛋白反应 (UPR) 来平衡内质网应激，UPR 被认为是典型的 ER 应激反应。 UPR 的特点是三种主要蛋白质，这些蛋白质会导致应激细胞中转录和翻译程序的特定变化。 UPR 的激活可以诱导细胞凋亡，也可以诱导细胞保护程序，例如自噬。人们越来越认识到 UPR 诱导的自噬在支持肿瘤发生和癌症治疗耐药性中所发挥的作用。最近报道了几种连接细胞应激、UPR 成分和自噬的新途径，它们一起可以被视为非典型的 ER 应激反应。在这里，我们回顾了经典和非经典 ER 应激反应激活细胞保护性自噬并促进肿瘤生长和治疗抵抗的分子机制的最新发现。自噬已被确定为一种可药物化的途径，但自噬的组成部分（ATG 基因）已被证明难以药物化。可能的情况是，针对 UPR 或非典型 ER 应激程序可以更有效地阻止细胞保护性自噬，从而增强癌症治疗。对这些途径的更深入了解可以为癌症提供新的治疗靶点。