Activation of the STING pathway potentiates the antitumor efficacy of doxorubicin in soft-tissue sarcoma.

Background: Systemic treatment of soft-tissue sarcoma (STS) relies on cytotoxic chemotherapy, with doxorubicin being the key therapeutic agent. However, immune activation is required for optimal antitumor effects of doxorubicin. This study investigated whether activation of the STING pathway enhances doxorubicin's antitumor effect in STS. Methods: STS cell lines were treated with doxorubicin to evaluate the activation of STING pathway. Deletion of Sting1 gene was employed to validate its role in mediating doxorubicin's effects. In a syngeneic mouse model of STS, doxorubicin was administered alone or in combination with a STING agonist ADU-S100. Tumor-infiltrating CD45+ cells were magnetically sorted for RNA sequencing to identify genes and pathways linked to STING activation. The upregulated genes were analyzed for their association with survival in the Cancer Genome Atlas Sarcoma (TCGA-SARC) patient cohort. Results: Doxorubicin induced cytosolic DNA leakage in STS cell lines, triggering the activation of STING pathway. Deletion of Sting1 attenuated doxorubicin-induced upregulation of proinflammatory cytokines in cells. In the syngeneic mouse model of STS, doxorubicin suppressed tumor growth, an effect significantly enhanced by coadministration of ADU-S100. RNA sequencing of tumor-infiltrating CD45+ cells revealed upregulation of immune pathways linked with STING signaling. In TCGA-SARC cohort, patients with higher expression of genes upregulated in the cells from STING-activated tumors exhibited improved survival, whereas those with lower expression showed poorer overall survival. Conclusion: Activation of STING pathway by ADU-S100 enhances the antitumor efficacy of doxorubicin in STS. Combining doxorubicin with STING agonists may be a promising therapeutic strategy worth exploring in future clinical trials.