Abstract Osteosarcoma (OS) is the most prevalent pediatric bone cancer, and standard of care treatment includes neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy. Several prognostic factors for overall survival have been identified, including 95% tumor necrosis at the time of primary surgery (surrogate of chemotherapy sensitivity) and the degree of inflammatory immune infiltrates in the tumor at diagnosis. We hypothesize that increasing the immune infiltrates in OS will improve tumor sensitivity to chemotherapy and overall survival. Our group has studied the impact of activating the cGAS-STING pathway in OS via intratumoral delivery of ADU-S100 — a potent STING agonist — in both murine and canine OS. ADU-S100 increases levels of pro-inflammatory cytokines and chemokines, including Tumor Necrosis Factor-α, Interferon-β, Interleukin-6, CCL5 and CXCL10 in the treated tumors. In addition, increased activated macrophage, T-, and B-cell infiltrates are observed. We hypothesized that combining the ADU-S100 STING agonist with chemotherapy could improve outcomes in our models of OS. As we have shown the effects of STING agonist to recruit T-cells into the tumor, we also incorporated immune checkpoint inhibitor (ICI) treatment (anti-PD1 and anti-CTLA4). We used the syngeneic murine OS cell line F420 to establish intratibial tumors in C57BL/6 mice. Once tumors were palpable, cohorts of mice were treated with ADU-S100 followed by carboplatin and ICI, comparing outcomes to the monotherapy and dual therapy control cohorts. ADU-S100 + carboplatin (standard OS chemotherapy in canines) or ADU-S100 + carboplatin + ICI significantly increases (P0.05) median survival compared to any of the treatments given as monotherapy. The addition of ICI to ADU-S100 + carboplatin appears to further extend the survival in responder mice. At day 40 post-tumor challenge, 46% of the ADU-S100 + carboplatin + ICI treated mice continue with disease control compared to 9% in the ADU-S100 + carboplatin treated cohort (P=0.035). Ongoing studies include combining ADU-S100 + ICI with doxorubicin, cisplatin, and methotrexate (standard of care chemotherapy agents given for OS in humans) and investigations of the mechanisms determining responder versus non-responder mice. Citation Format: Mayra L. Mendiola, Michele Doucet, Erin E. Resch, Brian H. Ladle. cGAS-STING pathway agonist plus immune checkpoint inhibitor augments chemotherapy effectiveness in murine osteosarcoma models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7802.
Mendiola et al. (Fri,) studied this question.