RT Journal Article SR Electronic T1 Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells JF bioRxiv FD Cold Spring Harbor Laboratory SP 2024.10.28.620471 DO 10.1101/2024.10.28.620471 A1 Herbst, Michael A1 Köksal, Hakan A1 Brunn, Silvan A1 Zanetti, Dominik A1 Domocos, Ioana A1 De Stefani, Viola A1 Pereira, Paulo A1 Nater, Marc A1 Cecconi, Virginia A1 van den Broek, Maries YR 2024 UL http://biorxiv.org/content/early/2024/10/31/2024.10.28.620471.abstract 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.