biostudies-literatureHe YNCI NIH HHSe2300688https://www.ebi.ac.uk/biostudies/studies/S-EPMC10964211biostudies-literatureUnknown12(24)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, a distinct CD4-mediated, protein-based combination therapy of STING and ICB as an in situ vaccine, is reported. The treatment eliminates subcutaneous MC38 and YUMM1.7 tumors in 70-100% of mice and protected all cured mice against rechallenge. Mechanistic studies reveal a robust T_H 1 polarization and suppression of T_reg of CD4⁺ T cells, followed by an effAdvanced healthcare materialsSTING Protein-Based In Situ Vaccine Synergizes CD4⁺ T, CD8⁺ T, and NK Cells for Tumor Eradication.PMC10964211P30 CA014051F99 CA274651R01 CA235375Huang SBelcher AMHe YKaskow JACovarrubias GPires ISSacane JCHammond PTHong CfalseSTING 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, a distinct CD4-mediated, protein-based combination therapy of STING and ICB as an in situ vaccine, is reported. The treatment eliminates subcutaneous MC38 and YUMM1.7 tumors in 70-100% of mice and protected all cured mice against rechallenge. Mechanistic studies reveal a robust T_H 1 polarization and suppression of T_reg of CD4⁺ T cells, followed by an eff2023-01-01T00:00:00Z2023 Sep2026-07-15T04:40:10.704Z2025-08-27T03:08:31.303ZS-EPMC109642113701572910.1002/adhm.202300688