The key findings of this study are that a selective protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) inhibitor, but not a mitogen-activated protein kinase 5 (ASK1, also known as MAP3K5) inhibitor, dramatically reduced the USP7i-induced phosphorylation of HSF1, indicating that PERK acts as a potential upstream kinase of HSF1 for maintaining cellular adaptation to various stress conditions, including cancer cell death caused by chemotherapy. Here, HSF1 is linked to cancer.