Enhancing the Effectiveness of Chemotherapy in Osteosarcoma by Targeting Tumour-Associated Macrophages (TAMs) through STING Activation

Osteosarcoma is an aggressive pediatric, adolescent, and young adult bone cancer with an immunosuppressive tumor microenvironment (TME) that limits immunotherapy efficacy. Tumor-associated macrophages, key players in immunosuppression and metastasis, are abundant in the osteosarcoma TME. The cGAS/STING pathway has emerged as a target for enhancing anti-tumor immunity. Here, this work investigates whether STING stimulation could reprogramme macrophages toward a tumoricidal M1-like phenotype and enhance doxorubicin efficacy against osteosarcoma. These results show that while doxorubicin induces cell death of osteosarcoma cells, it fails to activate STING in macrophages. However, pre-treatment of macrophages with a STING agonist enhances M1-like polarization of macrophages when indirectly co-cultured with chemotherapy-treated osteosarcoma cells, regardless of the original macrophage phenotype. Importantly, this work observes a loss of STING protein when cells are excessively stimulated with a STING agonist and sequential dosing offered no advantage over a single treatment. Finally, this work demonstrates that the combined therapy of doxorubicin and a single dose of neoadjuvant STING agonist synergistically increases osteosarcoma cell death via M1-macrophages compared to either therapy alone. These findings highlight the therapeutic potential of STING agonists to reprogram macrophages within the TME, and improve chemotherapy efficacy, offering a promising new strategy to enhance osteosarcoma treatment options.