Magnitude of Therapeutic STING Activation Determines CD8⁺ T Cell-Mediated Anti-tumor Immunity

STING pathway activation by intratumoral administration of cyclic dinucleotides (CDNs) results in stable tumor regression, yet the underlying innate and adaptive immune mechanisms are not fully established. ADU-S100, CDN under clinical evaluation, was used with an optimized dosing regimen to uncover key immune requirements for tumor regression. An immunogenic dose induces local expansion of tumor-specific CD8+ T cells, which are both necessary and sufficient for durable anti-tumor immunity and correlated with STING activation in hematopoietic but not tumor or stromal cells. Type I IFN, but not TNFα, drives optimal anti-tumor immune responses. The function of ADU-S100-induced CD8+ T cells was enhanced by combination with immune checkpoint modulators anti-PD-1 and anti-CTLA4. These results provide fundamental mechanistic insights into STING IT therapy