Project Summary

In studying the cGAS-STING pathway in T cells, we discovered that its activation induces a potent type I interferon response but also increases cell death and impairs proliferation. Consistent with these findings, STING agonists strongly suppress CAR-T cell function, limiting their direct use in adoptive therapy. Nevertheless, given STING’s ability to reprogram immunologically “cold” tumors into “hot” ones, we ablated STING in CAR-T cells and combined this with systemic STING activation, resulting in a robust synergistic antitumor effect in a murine pancreatic cancer model. Building on these findings, we will first use syngeneic tumor models to dissect how STING-deficient CAR-T cells, in combination with STING agonists, remodel the tumor microenvironment and promote antigen spreading to endogenous T cells. Second, we will incorporate mRNA vaccination to enhance CAR-T cell expansion and function while further promoting endogenous immune responses. Third, we will engineer STING-deficient CAR-T cells to produce and deliver cGAMP directly into the tumor, allowing for spatially confined STING activation while avoiding systemic toxicity. These complementary approaches will define the cellular mechanisms underlying STING-mediated synergy, benchmark STING-deficient CAR-T cells against other engineering strategies, and establish a platform for rational, controlled STING engagement in adoptive cell therapy.

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