Engineered T cell-agonist chimera for logic-gated STING activation and augmented cancer immunotherapy

The efficacy of adoptive T cell therapy against solid tumors is markedly hindered by the immunosuppressive microenvironment. Here, we demonstrate that stimulator of interferon genes (STING) activation in tumor-associated macrophages (TAM) enhances the intratumoral infiltration and cytotoxicity of adoptive T cells. We next design a TAM-targeted nanoagonist and engineer a T cell-agonist chimera (SNTC) via covalent surface anchoring, to achieve synchronized biodistribution of STING agonist with adoptive T cells. The nanoagonist is locally released in tumor tissue in response to the elevated reduction potential on T cell surface, followed by intracellular glutathione-mediated restoration of STING agonist in TAM, thereby enabling AND logic-gated STING activation. SNTC not only reshapes tumor stroma and immunosuppressive tumor microenvironment to augment adoptive T cell function but also enhances the antigen presentation ability of TAM to activate endogenous T cells. SNTC elicits robust antitumor efficacy in melanoma tumor-bearing mice, resulting in over 40% survival beyond 60 d. Moreover, combining tumor-infiltrating T lymphocyte (TIL)-based SNTC with immune checkpoint blockade therapy leads to sustained tumor regression in mouse model of orthotopic pancreatic tumor. Collectively, SNTC holds translational potential to optimize STING activation for adoptive T cell therapy of cancer.