Refractoriness of STING therapy can be oppressed by AKT inhibitor through effective tumor vascular disruption in primary tumor

Abstract

Stimulator of interferon genes (STING) promotes anti-tumor immunity by linking innate and adaptive immunity, but it remains unclear how intratumoral treatment with STING agonists yields anti-tumor effects. Here we demonstrate that intratumoral injection of the STING agonist cGAMP induces strong, rapid, and selective apoptosis of tumor endothelial cells (ECs) in implanted LLC tumor, melanoma and breast tumor, but not in spontaneous breast cancer and melanoma. In both implanted and spontaneous tumors, cGAMP greatly increases TNFα from tumor-associated myeloid cells. However, compared to spontaneous tumor ECs, implanted tumor ECs are more vulnerable to TNFα-TNFR1 signaling-mediated apoptosis, which promotes effective anti-tumor activity. The spontaneous tumor’s refractoriness to cGAMP is abolished by co-treatment with AKT 1/2 inhibitor (AKTi). Combined treatment with cGAMP and AKTi induces extensive tumor EC apoptosis, leading to extensive tumor apoptosis and marked growth suppression of the spontaneous tumor. These findings propose an advanced avenue for treating primary tumors that are refractory to single STING agonist therapy.