HE4 drives PD-L1 expression in myeloid cells via IFN-γR–JAK–STAT3 signaling to promote tumor immune evasion

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have achieved success in cancer therapy; however, most patients fail to respond, and many develop severe immune-related adverse events (irAEs). While interferon-γ (IFN-γ) is widely regarded as the canonical driver of PD-L1 expression, how PD-L1 is regulated in myeloid compartments of the tumor microenvironment (TME) remains incompletely understood. Here, we identified human epididymis protein 4 (HE4), a secreted glycoprotein that is overexpressed in multiple human cancers, as a previously unrecognized inducer of PD-L1 transcription in certain TMEs. Mechanistically, HE4 directly binds to interferon-γ receptors, activates JAK–STAT3 signaling, and upregulates PD-L1 expression. Neutralization of mouse or human HE4 with monoclonal antibodies markedly reduced PD-L1 expression on myeloid cells in the TME, restored CD8⁺ T-cell activity, and suppressed tumor growth in both syngeneic and humanized models. Importantly, HE4 blockade induced significantly fewer irAEs than PD-1 blockade did, suggesting its superior safety. Clinically, high HE4 expression predicts poor prognosis but is correlated with enhanced responsiveness to PD-1 inhibitors in lung adenocarcinoma patients, underscoring its translational significance as both a therapeutic target and a predictive biomarker. Together, these findings reveal that HE4 is a tumor-derived driver of immune evasion and establish HE4 blockade as a safer and clinically actionable immunotherapeutic strategy.