Targeted inhibition of ATR kinase promotes antitumor immunity in HNSCC through enhanced STING activation and T cell function

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OBJECTIVES: Oral cavity head and neck squamous cell carcinoma (HNSCC) represents a major global health burden, with over 40,000 new cases annually in the United States and >500,000 worldwide. Despite advances in surgery, radiation therapy, chemotherapy, and immunotherapy, overall survival rates have remained largely stagnant over the past three decades, and over half of patients ultimately die from the disease. Although immune checkpoint inhibitors (ICIs) have improved outcomes for a subset of patients with recurrent or metastatic HNSCC, the majority gain limited benefit. Thus, novel therapeutic strategies that enhance responses to immunotherapy are urgently needed. The ATR-CHK1 signaling pathway has recently been implicated in immune modulation, suggesting that ATR inhibition may potentiate antitumor immunity. This study investigates the therapeutic efficacy of the novel ATR inhibitor AZD6738, alone and in combination with anti-PD-1 therapy, in a syngeneic mouse model of HNSCC. MATERIALS AND METHODS: An orthotopic syngeneic mouse model was used to assess in vivo treatment efficacy. Immune profiling of tumors following AZD6738 treatment was performed by immunohistochemistry and flow cytometry. Conditioned medium from cocultures of tumor and bone marrow cells treated with AZD6738 was analyzed by flow cytometry to evaluate immune cell populations. Additional coculture experiments with bone marrow-derived cells and splenic T cells assessed T cell activation and proliferation. In vitro assays, including clonogenic survival, western blotting, and ATR shRNA knockdown, were used to confirm drug specificity and explore molecular mechanisms. RNA sequencing of tumor samples was conducted to evaluate cytokine expression and immune-related gene signatures. RESULTS: AZD6738 significantly enhanced the efficacy of anti-PD-1 therapy by remodeling the tumor microenvironment. Treatment increased cytotoxic T cell infiltration and activity while reducing regulatory T cells and immunosuppressive myeloid cells. ATR inhibition promoted M1 macrophage polarization and modulated cytokines supporting T cell activation. Mechanistically, enhanced immune responses were associated with DNA damage-induced activation of the cGAS/STING pathway and reduced STAT3 phosphorylation. Transcriptomic analyses revealed that combination therapy upregulated interferon signaling and suppressed epithelial-mesenchymal transition pathways in the MOC1 tumor model. CONCLUSION: AZD6738 enhances antitumor immunity through cytotoxic T cells and innate immune mechanisms, supporting its further development in combination with anti-PD-1 therapy for HNSCC.

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