Lewicky Jordan D, Martel Alexandrine L, Gupta Mukul Raj, Roy René, Rodriguez Galaxia M, Vanderhyden Barbara C, Le Hoang-Thanh
Health Sciences North Research Institute, 56 Walford Road, Sudbury, ON P3E 2H2, Canada.
Glycosciences and Nanomaterial Laboratory, Université du Québec à Montréal, Succ. Centre-Ville, Montréal, QC H3C 3P8, Canada.
Cancers (Basel). 2023 Aug 16;15(16):4127. doi: 10.3390/cancers15164127.
Many traditional cancer treatments such as radiation and chemotherapy are known to induce cellular DNA damage as part of their cytotoxic activity. The cGAS-STING signaling axis, a key member of the DNA damage response that acts as a sensor of foreign or aberrant cytosolic DNA, is helping to rationalize the DNA-damaging activity of these treatments and their emerging immunostimulatory capacity. Moreover, cGAS-STING, which is attracting considerable attention for its ability to promote antitumor immune responses, may fundamentally be able to address many of the barriers limiting the success of cancer immunotherapy strategies, including the immunosuppressive tumor microenvironment. Herein, we review the traditional cancer therapies that have been linked with cGAS-STING activation, highlighting their targets with respect to their role and function in the DNA damage response. As part of the review, an emerging "chemoimmunotherapy" concept whereby DNA-damaging agents are used for the indirect activation of STING is discussed as an alternative to the direct molecular agonism strategies that are in development, but have yet to achieve clinical approval. The potential of this approach to address some of the inherent and emerging limitations of cGAS-STING signaling in cancer immunotherapy is also discussed. Ultimately, it is becoming clear that in order to successfully employ the immunotherapeutic potential of the cGAS-STING axis, a balance between its contrasting antitumor and protumor/inflammatory activities will need to be achieved.
许多传统的癌症治疗方法，如放疗和化疗，已知会诱导细胞DNA损伤，这是其细胞毒性活性的一部分。cGAS-STING信号轴是DNA损伤反应的关键成员，作为外来或异常胞质DNA的传感器，有助于解释这些治疗方法的DNA损伤活性及其新出现的免疫刺激能力。此外，cGAS-STING因其促进抗肿瘤免疫反应的能力而备受关注，它可能从根本上解决许多限制癌症免疫治疗策略成功的障碍，包括免疫抑制性肿瘤微环境。在此，我们综述了与cGAS-STING激活相关的传统癌症治疗方法，强调了它们在DNA损伤反应中的作用和功能方面的靶点。作为综述的一部分，讨论了一种新兴的“化学免疫疗法”概念，即使用DNA损伤剂间接激活STING，作为正在开发但尚未获得临床批准的直接分子激动剂策略的替代方法。还讨论了这种方法解决癌症免疫治疗中cGAS-STING信号传导一些固有和新出现的局限性的潜力。最终，越来越明显的是，为了成功利用cGAS-STING轴的免疫治疗潜力，需要在其相反的抗肿瘤和促肿瘤/炎症活性之间取得平衡。
