Lack or loss of tumor antigenicity represents one of the key mechanisms of immune escape and resistance to T cell–based immunotherapies. Evidence suggests that activation of stimulator of interferon genes (STING) signaling in tumor cells can augment their antigenicity by triggering a type I IFN-mediated sequence of autocrine and paracrine events. Although suppression of this pathway in melanoma and other tumor types has been consistently reported, the mechanistic basis remains unclear. In this study, we asked whether this suppression is, in part, epigenetically regulated and whether it is indeed a driver of melanoma resistance to T cell–based immunotherapies. Using genome-wide DNA methylation profiling, we show that promoter hypermethylation of cGAS and STING genes mediates their coordinated transcriptional silencing and contributes to the widespread impairment of the STING signaling function in clinically-relevant human melanomas and melanoma cell lines. This suppression is reversible through pharmacologic inhibition of DNA methylation, which can reinstate functional STING signaling in at least half of the examined cell lines. Using a series of T cell recognition assays with HLA-matched human melanoma tumor-infiltrating lymphocytes (TIL), we further show that demethylation-mediated restoration of STING signaling in STING-defective melanoma cell lines can improve their antigenicity through the up-regulation of MHC class I molecules and thereby enhance their recognition and killing by cytotoxic T cells. These findings not only elucidate the contribution of epigenetic processes and specifically DNA methylation in melanoma-intrinsic STING signaling impairment but also highlight their functional significance in mediating tumor-immune evasion and resistance to T cell–based immunotherapies.

肿瘤抗原性的缺乏或丧失代表了免疫逃逸和对基于 T 细胞的免疫疗法的抵抗的关键机制之一。有证据表明，肿瘤细胞中干扰素基因刺激因子 (STING) 信号的激活可以通过触发 I 型 IFN 介导的自分泌和旁分泌事件序列来增强其抗原性。尽管在黑色素瘤和其他肿瘤类型中抑制该途径的报道一直存在，但其机制基础仍不清楚。在这项研究中，我们询问了这种抑制是否部分受表观遗传调控，以及它是否确实是黑色素瘤对基于 T 细胞的免疫疗法产生抗性的驱动因素。使用全基因组 DNA 甲基化分析，我们表明cGAS和STING 的启动子高甲基化基因介导其协调的转录沉默，并导致临床相关人类黑色素瘤和黑色素瘤细胞系中 STING 信号功能的广泛受损。这种抑制是通过药理学抑制 DNA 甲基化来逆转的，这可以在至少一半的检查细胞系中恢复功能性 STING 信号。使用与 HLA 匹配的人黑色素瘤肿瘤浸润淋巴细胞 (TIL) 的一系列 T 细胞识别测定，我们进一步表明，去甲基化介导的 STING 缺陷黑色素瘤细胞系中 STING 信号的恢复可以通过上调MHC I 类分子，从而增强它们对细胞毒性 T 细胞的识别和杀伤。