ArticleScience advances2025
Noncanonical UPR factor CREB3L2 drives immune evasion of triple-negative breast cancer through Hedgehog pathway modulation in T cells.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Multifunctional nanotherapeutics for targeted modulation of endoplasmic reticulum stress to potentiate cancer therapy.Asian journal of pharmaceutical sciences · 2026Review
- A Multi-Omics Framework Reveals Tumor Heterogeneity and Predicts Therapeutic Targets in Renal Cell Carcinoma.International journal of molecular sciences · 2026Article
- WDR82 suppresses breast cancer progression by inhibiting ERK-driven chemokine expression and neutrophil infiltration.International journal of biological sciences · 2026Article
- Signalling Pathways and Inhibitors in Triple Negative Breast Cancer: Current Progress.Anti-cancer agents in medicinal chemistry · 2026Review
- Regulatory T cells in the breast cancer tumor microenvironment: new mechanisms, potential therapeutic strategies and future perspectives.American journal of cancer research · 2026Review
- The Unfolded Protein Response-Novel Mechanisms, Challenges, and Key Considerations for Therapeutic Intervention.Cancers · 2025Review
- Investigating the role of tumor cell heterogeneity and angiogenesis genes in the prognosis of multiple myeloma.Frontiers in immunology · 2025Article
- Immunotherapy resistance in triple-negative breast cancer: Molecular mechanisms, tumor microenvironment, and therapeutic implications.Frontiers in oncology · 2025Review
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Authors and funding
10 authors.
Funding
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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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Registered trials
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