STING Protein-based in situ Vaccine Synergizes CD4 + T, CD8 + T and NK Cells for Tumor Eradication.

Stimulator of interferon genes (STING) signaling is a promising target in cancer immunotherapy, with many ongoing clinical studies in combination with immune checkpoint blockade (ICB). Existing STING-based therapies largely focus on activating CD8 + T cell or NK cell-mediated cytotoxicity, while the role of CD4 + T cells in STING signaling has yet to be extensively studied in vivo. Here, we report a distinct CD4-mediated, protein-based combination therapy of STING and ICB as an in situ vaccine. The treatment eliminated subcutaneous MC38 and YUMM1.7 tumors in 70%-100% of mice and protected all cured mice against rechallenge. Mechanistic studies revealed a robust T H 1 polarization and suppression of T reg of CD4 + T cells, followed by an effective collaboration of CD4 + T, CD8 + T and NK cells to eliminate tumors. Finally, we demonstrated the potential to overcome host STING deficiency by significantly decreasing MC38 tumor burden in STING-KO mice, addressing the translational challenge for the 19% of human population with loss-of-function STING variants. This article is protected by copyright. All rights reserved.