Vasiyani Hitesh
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23284, USA.
Apoptosis. 2026 Feb 9;31(2):68. doi: 10.1007/s10495-026-02283-5.
Immunotherapy has drawn attention in the current era; CAR T cells and STING agonists are emerging as novel approaches for cancer treatment. Advances in STING agonist development are ongoing, and many remain in the preclinical stage. At the same time, it is now clear that dysregulated or chronic activation of the cGAS-STING pathway contributes to a broad spectrum of human pathological conditions. Classically, cGAS, as a sensor of dsDNA, recognizes the cytoplasmic dsDNA and, due to the enzymatic activity, generates a di-nucleotide molecule as the 2'3' cGAMP. 2'3' cGAMP behaves as the natural activator of STING and further facilitates the downstream pathway via TBK1 to IRF-3 and NF-κB. Conventionally, this pathway is explored in the context of the antiviral immune response. The agonists of STING have a distinct role in immunotherapy, but the cGAS-STING pathway is also associated with other molecular mechanisms that deviate from its canonical pathway and activate its non-canonical pathway, which leads to different molecular patterns, and this is associated with many diseases and cancer survival. Here, we discussed the various pathways that regulate the cGAS-STING activation in chronic and non-canonical ways. Chronic and non-canonical pathways associated with human disease and cancer. We also discussed the therapeutic opportunities.
免疫疗法在当今时代备受关注；嵌合抗原受体T细胞（CAR T细胞）和干扰素基因刺激蛋白（STING）激动剂正成为癌症治疗的新方法。STING激动剂的研发工作仍在推进，许多仍处于临床前阶段。与此同时，现在很清楚的是，环磷酸鸟苷-腺苷酸合成酶（cGAS）-STING通路的失调或慢性激活会导致多种人类病理状况。传统上，cGAS作为双链DNA（dsDNA）的传感器，识别细胞质中的dsDNA，并因其酶活性产生一种二核苷酸分子，即2'3'环磷酸鸟苷-腺苷酸（2'3' cGAMP）。2'3' cGAMP作为STING的天然激活剂，进一步通过TANK结合激酶1（TBK1）促进下游通路至干扰素调节因子3（IRF-3）和核因子κB（NF-κB）。传统上，这条通路是在抗病毒免疫反应的背景下进行研究的。STING激动剂在免疫疗法中具有独特作用，但cGAS-STING通路也与其他偏离其经典通路并激活其非经典通路的分子机制相关，这会导致不同的分子模式，并且这与许多疾病和癌症存活情况有关。在此，我们讨论了以慢性和非经典方式调节cGAS-STING激活的各种通路。与人类疾病和癌症相关的慢性和非经典通路。我们还讨论了治疗机会。
