STING Protein‐Based In Situ Vaccine Synergizes CD4+ T, CD8+ T, and NK Cells for Tumor Eradication

Yanpu He, Celestine Hong, Shengnan Huang, Justin A. Kaskow, Gil Covarrubias, Ivan S. Pires, James C. Sacane, Paula T. Hammond, Angela M. Belcher

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 TH 1 polarization and suppression of Treg 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.