Background: The cyclic GMP-AMP synthase (cGAS)–type I interferon (IFN-I) pathway detects cytoplasmic DNA and triggers immune responses. Cancer cells often suppress this pathway to evade immune surveillance; however, its therapeutic potential remains unclear.Methods: Mouse oral squamous cell carcinoma models, representing a prominent subtype of head and neck squamous cell carcinoma (HNSCC), were employed in this study. Flow cytometry, Western blot, ELISA, and PCR were used for analysis.Results: We found that immune-unresponsive MOC2 tumors exhibited a deficiency of antigen-presenting cells and cytotoxic T lymphocytes, along with a significant suppression of the cGAS-IFN-I pathway, compared to immune-responsive MOC1 tumors. An MOC2-conditioned medium impaired the differentiation of bone marrow-derived cells into dendritic cells (DCs), reducing the expression of DC markers as well as class I and II major histocompatibility complex (MHC) molecules. The activation of the cGAS-IFN-I pathway in MOC2 cells, either through exogenous DNA or direct IFN-I expression, enhanced class I MHC expression and antigen presentation on MOC2 cells. Furthermore, IFNB1 expression in MOC2 cells induced apoptosis and upregulated chemokines, such as CXCL9 and CXCL10, which recruit immune cells. In immunocompetent mice, IFNB1 expression suppressed MOC2 tumor growth by attracting DCs and T cells, an effect amplified by co-expressing the granulocyte–macrophage colony-stimulating factor.Conclusions: These findings highlight the potential of enhancing cancer cell-intrinsic cGAS-IFN-I signaling to improve tumor immune surveillance and control the progression of immune-cold HNSCC tumors.
背景：环状GMP-AMP合成酶（cGAS）-I型干扰素（IFN-I）通路可检测细胞质DNA并触发免疫应答。癌细胞常抑制该通路以逃避免疫监视，但其治疗潜力尚不明确。 方法：本研究采用小鼠口腔鳞状细胞癌模型，该模型是头颈部鳞状细胞癌（HNSCC）的重要亚型。通过流式细胞术、蛋白质印迹、酶联免疫吸附测定及聚合酶链反应进行分析。 结果：研究发现，与免疫应答型MOC1肿瘤相比，免疫无应答型MOC2肿瘤表现出抗原呈递细胞和细胞毒性T淋巴细胞缺失，并显著抑制cGAS-IFN-I通路。MOC2条件培养基会损害骨髓来源细胞向树突状细胞（DC）的分化，降低DC标志物及I类和II类主要组织相容性复合体（MHC）分子的表达。通过外源DNA或直接表达IFN-I激活MOC2细胞中的cGAS-IFN-I通路，可增强I类MHC表达和MOC2细胞的抗原呈递能力。此外，MOC2细胞中IFNB1的表达可诱导细胞凋亡，并上调趋化因子（如CXCL9和CXCL10）以招募免疫细胞。在免疫健全小鼠中，IFNB1表达通过吸引DC和T细胞抑制MOC2肿瘤生长，该效应在与粒细胞-巨噬细胞集落刺激因子共表达时进一步增强。 结论：这些发现凸显了增强癌细胞内在cGAS-IFN-I信号传导在改善肿瘤免疫监视、控制免疫冷型HNSCC肿瘤进展方面的潜力。
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