2. Academic Validation
  3. HE4 drives PD-L1 expression in myeloid cells via IFN-γR-JAK-STAT3 signaling to promote tumor immune evasion

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

  • Cell Rep Med. 2026 Apr 21;7(4):102691. doi: 10.1016/j.xcrm.2026.102691.
Bo Zeng 1,  Yingying Zhou 2,  Heping Wang 2,  Panyin Shu 3,  Ting Pan 3,  Fangfang Liu 4,  Yangyang Li 2,  Ming Yi 2,  Ruirui He 5,  Lingyun Feng 2,  Zhihui Cui 2,  Guoling Huang 3,  Yanyun Du 5,  Xi Li 3,  Chuwen Chen 6,  Qian Chu 4,  Yuan Wang 7,  Xue Xiao 8,  Chenhui Wang 9
Affiliations

Affiliations

  • 1 The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China. Electronic address: [email protected].
  • 2 The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China.
  • 3 School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China.
  • 4 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 5 The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China; Personalized Drug Research and Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, Chengdu 610072, China.
  • 6 West China Second University Hospital of Sichuan University, Chengdu, Sichuan, China.
  • 7 The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China. Electronic address: [email protected].
  • 8 Department of Pathology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China. Electronic address: [email protected].
  • 9 The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China; Personalized Drug Research and Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, Chengdu 610072, China; Chuan-Yu Joint Key Laboratory for Pathological and Laboratory Medicine, Jinfeng Laboratory, Chongqing 400039, China. Electronic address: [email protected].
PMID: 41861828 DOI: 10.1016/j.xcrm.2026.102691
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.

Keywords

IFN-γR-JAK-STAT3 axis; anti-tumor immunity; human epididymis protein 4; immune-related adverse events; programmed cell death ligand 1; tumor immune evasion.

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