2. Academic Validation
  3. Noncanonical UPR factor CREB3L2 drives immune evasion of triple-negative breast cancer through Hedgehog pathway modulation in T cells

Noncanonical UPR factor CREB3L2 drives immune evasion of triple-negative breast cancer through Hedgehog pathway modulation in T cells

  • Sci Adv. 2025 Jan 10;11(2):eads5434. doi: 10.1126/sciadv.ads5434.
Zi-Jian Cao 1 2,  Jia You 3,  Yu-Meng Fan 1 2,  Jia-Ying Yang 1 2 4,  Jirui Sun 5 6,  Xiuli Ma 7,  Jinku Zhang 5 6,  Zhongwu Li 7 8,  Xiang Wang 9,  Yu-Xiong Feng 1 2
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, China.
  • 3 School of Life Sciences, Westlake University, Hangzhou, China.
  • 4 K2 Oncology Co., Ltd., Beijing, China.
  • 5 Department of Pathology, First Central Hospital of Baoding, Baoding, China.
  • 6 Hebei Key Laboratory of Molecular Pathology and Early Diagnosis of Tumor, Baoding, China.
  • 7 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China.
  • 8 Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Cancer Hospital, Hohhot, China.
  • 9 Zhejiang Key Laboratory of Integrated Oncology and Intelligent Medicine, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China.
PMID: 39792663 DOI: 10.1126/sciadv.ads5434
Abstract

The unfolded protein response (UPR) pathway is crucial for tumorigenesis, mainly by regulating Cancer cell stress responses and survival. However, whether UPR factors facilitate cell-cell communication between Cancer cells and immune cells to drive Cancer progression remains unclear. We found that adenosine 3',5'-monophosphate response element-binding protein 3-like protein 2 (CREB3L2), a noncanonical UPR factor, is overexpressed and activated in triple-negative breast Cancer, where its cleavage releases a C-terminal fragment that activates the Hedgehog pathway in neighboring CD8+ T cells. The enhanced Hedgehog pathway represses CD8+ T cell activation and inhibits its cytotoxic effects. Consequently, overexpression of CREB3L2 not only promotes tumor growth but also causes resistance to Immune Checkpoint blockade (ICB). Inhibition of the Hedgehog pathway impedes the growth of CREB3L2-overexpressed tumors and sensitizes them to ICB therapy. In summary, we identified a previously unidentified mechanism by which the UPR pathway dictates cross-talk between Cancer cells and immune cells, providing important Anticancer therapeutic opportunities.

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