ARTN drives CD8+ T cell exhaustion via the GFRα3-RET-PI3K/AKT Axis to promote TNBC progression

  • Cell Signal. 2026 May:141:112397. doi: 10.1016/j.cellsig.2026.112397.
Dongke Yan  1 ,  Yongling Wang  2 ,  Lei Zhang  1 ,  Yu Li  1 ,  Yanchao Gong  3 ,  Hongbin Liu  1 ,  Xiaobao Ma  1 ,  Jingjie Pang  4
Affiliations
  • 1. College of Biological and Environmental Engineering, Tianjin Vocational Institute, Tianjin 300410, China.
  • 2. Tianjin Ocean Pal Carol Biotech Co., Ltd, Tianjin 300350, China.
  • 3. College of Environment and Chemical Engineering, Tianjin Bohai Vocational Technology College, Tianjin 300402, China.
  • 4. Henan Normal University, College of Life Sciences, 46 Jianshe Road, Xinxiang City, Henan Province 453007, China. Electronic address: [email protected].
PMID: 41610967 DOI: 10.1016/j.cellsig.2026.112397
Abstract

Background: Triple-negative breast Cancer (TNBC) is an aggressive subtype with limited therapies. CD8+ T cell exhaustion drives TNBC immune escape, but mechanisms remain unclear. Artemin (ARTN), a secreted protein overexpressed in cancers, its role in regulating CD8+ T cells in TNBC tumor microenvironment is unknown.

Objective: To investigate whether ARTN promotes TNBC progression by inducing CD8+ T cell exhaustion and clarify the underlying molecular mechanisms.

Methods: Bioinformatics analyzed ARTN expression/prognostic value in TNBC. In vitro, ARTN knockdown/overexpression TNBC cells were used with Transwell, flow cytometry, and co-culture assays. Co-IP, Western blot, and gene knockdown identified ARTN's receptor and signaling in CD8+ T cells. In vivo, BALB/c mouse xenografts and RET Inhibitor intervention verified ARTN's function.

Results: ARTN was highly expressed in TNBC and correlated with poor prognosis. It promoted TNBC cell proliferation/invasion, inhibited Apoptosis, and induced CD8+ T cell exhaustion (upregulated PD-1/TIM-3, increased TGF-β/IL-10). Mechanistically, ARTN bound GFRα3-RET on CD8+ T cells, activating PI3K/Akt. GFRα3/RET knockdown or RET Inhibitor reversed these effects in vitro and in vivo.

Conclusion: This is the first study revealing ARTN induces CD8+ T cell exhaustion via GFRα3-RET-PI3K/Akt axis, promoting TNBC immune escape and progression. The ARTN-RET axis is a key immunosuppressive pathway, providing a potential target for combined immunotherapies.

Keywords
ARTN; CD8(+) T cell exhaustion; GFRα3-RET; PI3K/AKT signaling pathway; TNBC.
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