Decoding Endoplasmic Reticulum Stress Signals in Cancer Cells and Anti-tumor Immunity

The tumor microenvironment provokes endoplasmic reticulum (ER) stress in malignant cells and infiltrating immune populations. Sensing and responding to ER stress is coordinated by the unfolded protein response (UPR), an integrated signaling pathway governed by three ER stress sensors: activating transcription factor (ATF6), inositol-requiring enzyme 1 α (IRE1α), and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Persistent UPR activation modulates malignant progression, tumor growth, metastasis, and protective anti-tumor immunity. Hence, therapies targeting ER stress signaling can be harnessed to elicit direct tumor killing and concomitant anti-cancer immunity. Here, we highlight recent findings on the role of the ER stress responses in onco-immunology, with an emphasis on genetic vulnerabilities that render tumors highly sensitive to therapeutic UPR modulation.