In sharp contrast to observations in HCC, evidence from melanoma demonstrates that, under endoplasmic reticulum (ER) stress—a condition frequently experienced by cancer cells—SIRT7 robustly enhances PD-L1 expression by orchestrating alternative stress-responsive transcriptional programs, independent of MEF2A, and linked to activation of the unfolded protein response (UPR), a central adaptive pathway that mitigates ER stress and restores ER homeostasis. The gene discussed is SIRT7; the disease is hepatocellular carcinoma.