Abstract

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have achieved clinical success, yet most patients fail to respond and many develop immune-related adverse events (irAEs). Although interferon gamma (IFN-γ) is considered the canonical driver of PD-L1 expression, regulation of PD-L1 in myeloid cells within the tumor microenvironment (TME) remains poorly defined. Here, we identify human epididymis protein 4 (HE4), a tumor-secreted glycoprotein overexpressed in multiple cancers, as an unrecognized inducer of myeloid PD-L1 transcription. HE4 directly binds IFN-γ receptors, activates JAK-STAT3 signaling, and upregulates PD-L1. Neutralization of mouse or human HE4 with monoclonal antibodies reduced myeloid PD-L1 expression, restored CD8 + T cell activity, and suppressed tumor growth in syngeneic and humanized models, while inducing fewer irAEs than PD-1 blockade. Clinically, high HE4 expression predicts poor prognosis but correlates with improved response to PD-1 inhibitors in lung adenocarcinoma, highlighting HE4 as both a therapeutic target and predictive biomarker.