PT  - JOURNAL ARTICLE
AU  - Herbst, Michael
AU  - Köksal, Hakan
AU  - Brunn, Silvan
AU  - Zanetti, Dominik
AU  - Domocos, Ioana
AU  - De Stefani, Viola
AU  - Pereira, Paulo
AU  - Nater, Marc
AU  - Cecconi, Virginia
AU  - van den Broek, Maries
TI  - Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8<sup>+</sup> T cells
AID  - 10.1101/2024.10.28.620471
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.10.28.620471
4099  - http://biorxiv.org/content/early/2024/10/31/2024.10.28.620471.short
4100  - http://biorxiv.org/content/early/2024/10/31/2024.10.28.620471.full
AB  - Using a mouse tumor model with inducible cancer-cell-intrinsic cGAS expression, we show that cancer-cell-derived cGAMP is essential and sufficient to trigger a sustained type I interferon response within the tumor microenvironment. This led to improved CD8+ T cell-dependent tumor restriction. However, cGAMP limits the proliferation, survival, and function of STING-expressing but not of STING-deficient CD8+ T cells. In vivo, STING deficiency in CD8+ T cells enhanced tumor restriction. Consequently, cancer-cell-derived cGAMP both drives and limits the anti-tumor potential of CD8+ T cells. Mechanistically, T cell-intrinsic STING is associated with pro-apoptotic and antiproliferative gene signatures. Our findings suggest that STING signaling acts as a checkpoint in CD8+ T cells that balances tumor immunity.Competing Interest StatementThe authors have declared no competing interest.