Plain Language SummaryNatural killer (NK) cells play a critical role in our innate immune defense against tumors without prior exposure to cancer cells and, therefore, make an attractive instrument to harness antitumoral immunity as novel immunotherapies. Hodgkin lymphoma (HL) typically lacks major histocompatibility complex class I which is a requirement for an antigen-specific recognition of effector T cells but not for the NK cell antitumoral function. NK cells are dysfunctional in HL patients mainly due to upregulation of immune checkpoint PD-1 expression that inhibits immune cells effector functions. However, the mechanisms underpinning PD-1 expression and NK cell dysfunction remain unknown. In this study, we uncovered the mechanism by which immune checkpoint PD-1 expression is upregulated upon activation of the endonuclease IRE1α to rapidly change the abundance of key regulatory molecules including a small noncoding regulatory RNA (microRNA-34a) and the transcription factor XBP1. The IRE1α endonuclease plays a dual role in regulating the XBP1/miRNA-34a axis and PD-1 expression within NK cells, which is disrupted in patients with HL. IRE1α pathway in NK cells represents a potential target to optimize NK cell immune functions in future HL treatments.