Abstract 6175: Sting pathway activation potentiates the antitumor efficacy of doxorubicin in soft-tissue sarcoma

Abstract Background: Systemic treatment for soft-tissue sarcoma (STS) primarily relies on cytotoxic chemotherapy. Doxorubicin remains the key agent for systemic treatment in STS, as effective targeted treatment is unavailable and immune checkpoint inhibitors have shown limited efficacy. This study investigated whether activation of the STING pathway could enhance the antitumor effect of doxorubicin in STS. Methods: STS cell lines were treated with doxorubicin to assess STING pathway activation, with Sting1 gene deletion used to validate its essential role. In a syngeneic mouse model of STS, the STING agonist ADU-S100 was administered intratumorally in combination with doxorubicin. Tumor-infiltrating CD45+ immune cells were magnetically sorted for RNA sequencing to identify differentially expressed genes and enriched pathways linked to STING activation. These immune-related genes were analyzed for their association with survival in the TCGA-SARC patient cohort. Results: Doxorubicin treatment in STS cell lines induced cytosolic DNA leakage, triggering STING pathway activation. Sting1 gene deletion in cells attenuated this doxorubicin-induced activation, but did not impact cell proliferation in vitro. In a syngeneic mouse model, doxorubicin suppressed tumor growth in vivo, an effect further enhanced by intratumoral co-administration of ADU-S100. RNA sequencing of CD45+ tumor-infiltrating immune cells revealed upregulation immune response pathways linked with STING signaling. In the TCGA-SARC cohort, patients with higher expression of genes upregulated in STING-activated tumors exhibited improved survival, while those with lower expression showed poorer overall survival. Conclusion: STING pathway activation by ADU-S100 enhances the antitumor efficacy of doxorubicin in STS, suggesting that combining doxorubicin with ADU-S100 may be a promising strategy for future clinical trials. Citation Format: Wonyoung Choi, Gi Yeon Lee, Sun-Young Kong. Sting pathway activation potentiates the antitumor efficacy of doxorubicin in soft-tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6175.