The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient DCs improves the efficacy of both adoptive T cell therapy and anti–PD-1 immunotherapy for “cold tumors,” which exhibit poor therapeutic responses. This effect did not depend on prolonged survival of vaccinated DCs, but on tumor-derived DNA that activates STING-dependent type I IFN secretion and subsequent production of CXCL10 to recruit CD8⁺ T cells. Additionally, loss of AIM2-dependent IL-1β and IL-18 processing enhanced the treatment response further by limiting the recruitment of regulatory T cells. Finally, AIM2 siRNA-treated mouse DCs in vivo and human DCs in vitro enhanced similar anti-tumor immune responses. Thus, targeting AIM2 in tumor-infiltrating DCs is a promising new treatment strategy for melanoma.

中文翻译：

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AIM2调节抗肿瘤免疫，是黑色素瘤的可行治疗靶点

黑色素瘤 2 (AIM2) 通路中的 STING 和缺失通路因胞质 DNA 的存在而被激活，而 STING 激动剂可增强免疫治疗反应。在这里，我们表明 AIM2 在人类黑色素瘤中的树突状细胞 (DC) 表达与不良预后相关，并且与 STING 相比，AIM2 在黑色素瘤微环境中发挥免疫抑制作用。用 AIM2 缺陷型 DC 接种疫苗可提高过继性 T 细胞疗法和抗 PD-1 免疫疗法对治疗反应不佳的“冷肿瘤”的疗效。这种效应不依赖于接种疫苗的 DC 的存活时间延长，而是依赖于激活 STING 依赖性 I 型 IFN 分泌的肿瘤衍生 DNA 和随后产生 CXCL10 以募集 CD8 ⁺T细胞。此外，AIM2 依赖性 IL-1β 和 IL-18 加工的丧失通过限制调节性 T 细胞的募集进一步增强了治疗反应。最后，AIM2 siRNA 处理的体内小鼠 DC 和体外人类 DC 增强了相似的抗肿瘤免疫反应。因此，在肿瘤浸润性 DCs 中靶向 AIM2 是一种有前途的黑色素瘤新治疗策略。