不同的先天免疫途径汇聚到干扰素基因刺激器（STING），并在识别细胞中的异常核酸后触发 I 型干扰素反应。这种非冗余功能使 STING 成为免疫监视领域的主要参与者，也是癌症和传染病治疗的新兴靶标。除了癌症中经常发生的体细胞突变之外，编码 STING 蛋白的人类基因 TMEM173 (STING1) 具有很大的遗传异质性； R232、HAQ (R71H-G230A-R293Q) 和 H232 是最常见的等位基因。尽管其中一些等位基因可能是亚等位基因，但由于现有的功能评估是在有偏见的生物系统中进行的，因此它们的功能仍然存在争议。在这里，通过使用遗传背景匹配模型，我们报告了 R232、HAQ 和 H232 变体对 STING 功能的功能评估，以及这些基因型如何影响对临床相关病毒的易感性，从而支持了导致基因组间差异的潜在原因。 - 对感染的个人反应。我们的研究结果还证明了 STING 在调节单核细胞功能和分化为巨噬细胞方面具有一种新的不依赖于 Toll 样受体的作用。我们通过证明携带 H232 等位基因的单核细胞在 M1/M2 分化、干扰素反应和抗原呈递方面如何受损，进一步支持了 STING1 变体与人类生物学的相互作用。最后，我们评估了一小群根据 STING 基因型分层的黑色素瘤患者对 PD-1 抑制剂的反应。鉴于 STING 蛋白在检测 DNA 病毒、细菌病原体和错位的癌症 DNA 方面的贡献，这些数据可能支持开发针对传染病和癌症的新型治疗方案。© 2023。作者。

Different innate immune pathways converge to Stimulator of interferon genes (STING) and trigger type I interferon responses after recognition of abnormal nucleic acids in the cells. This non-redundant function renders STING a major player in immunosurveillance, and an emerging target for cancer and infectious diseases therapeutics. Beyond somatic mutations that often occur in cancer, the human gene encoding STING protein, TMEM173 (STING1), holds great genetic heterogeneity; R232, HAQ (R71H-G230A-R293Q) and H232 are the most common alleles. Although some of these alleles are likely to be hypomorphic, their function is still debated, due to the available functional assessments, which have been performed in biased biological systems. Here, by using genetic background-matched models, we report on the functional evaluation of R232, HAQ and H232 variants on STING function, and on how these genotypes affect the susceptibility to clinically relevant viruses, thus supporting a potential contributing cause to differences in inter-individual responses to infections. Our findings also demonstrate a novel toll-like receptor-independent role of STING in modulating monocytic cell function and differentiation into macrophages. We further supported the interplay of STING1 variants and human biology by demonstrating how monocytes bearing the H232 allele were impaired in M1/M2 differentiation, interferon response and antigen presentation. Finally, we assessed the response to PD-1 inhibitor in a small cohort of melanoma patients stratified according to STING genotype. Given the contribution of the STING protein in sensing DNA viruses, bacterial pathogens and misplaced cancer DNA, these data may support the development of novel therapeutic options for infectious diseases and cancer.© 2023. The Author(s).