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

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.

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

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.

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.

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.