ERRα-ETV5 axis drives PD-L1 upregulation and immune escape in gallbladder cancer

  • Cancer Lett. 2026 May 28:646:218386. doi: 10.1016/j.canlet.2026.218386.
Lei Wang  1 ,  SiJia Wen  2 ,  Wanwan Gong  2 ,  Fan Wu  2 ,  Mengmeng Yang  3 ,  Xinyi Lu  4 ,  Xingmei Guo  5 ,  Ping Sun  5 ,  Yu Chen  6 ,  Daozhen Chen  7 ,  Hui Zhao  8
Affiliations
  • 1. Department of Hepatopancreatobiliary Surgery, Jiangnan University Medical Center, Wuxi, China; Institute for Reproductive Health and Genetic Diseases, Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China; Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China; Department of Hepatopancreatobiliary Surgery, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China.
  • 2. Department of Hepatopancreatobiliary Surgery, Jiangnan University Medical Center, Wuxi, China.
  • 3. Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China.
  • 4. Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China.
  • 5. Pathology Department, Jiangnan University Medical Center, Wuxi, China.
  • 6. Institute for Reproductive Health and Genetic Diseases, Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China. Electronic address: [email protected].
  • 7. Institute for Reproductive Health and Genetic Diseases, Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Wuxi, China; Institute for Reproductive Health and Genetic Diseases, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, China; Wuxi Higher Health Vocational Technology School, Wuxi, China. Electronic address: [email protected].
  • 8. Department of Hepatopancreatobiliary Surgery, Jiangnan University Medical Center, Wuxi, China. Electronic address: [email protected].
PMID: 41791643 DOI: 10.1016/j.canlet.2026.218386
Abstract

Gallbladder Cancer (GBC) is a highly aggressive malignancy with a poor response to immune checkpoint blockade (ICB), highlighting an urgent need to understand the mechanisms of immune evasion. We identified the Orphan Nuclear Receptor ERRα as a critical regulator of the immunosuppressive tumor microenvironment in GBC. Mechanistically, we discovered that ERRα transcriptionally upregulates the ETS-family transcription factor ETV5, which in turn directly binds to and activates the PD-L1 (CD274) promoter, establishing a novel ERRα-ETV5-PD-L1 signaling axis.​ In clinical specimens, ERRα expression positively correlated with PD-L1 levels and served as an independent prognostic factor for poor survival. Using a combination of human GBC tissues, in vitro co-culture systems, and a humanized mouse model, we demonstrated that genetic or pharmacological inhibition of ERRα downregulated PD-L1 and potentiated CD8+ T cell-mediated cytotoxicity.​ Critically, combined targeting of ERRα (using the inverse agonist XCT790) and PD-L1 (using durvalumab) synergistically suppressed tumor growth and enhanced intratumoral T cell infiltration in vivo. Our findings reveal ERRα as a master transcriptional regulator of immune evasion and highlight the therapeutic potential of co-inhibiting the ERRα-ETV5-PD-L1 axis to overcome immunotherapy resistance in GBC.

Keywords
Durvalumab; ERRα; ETV5; Gallbladder cancer; Immune escape; PD-L1.
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