Li Chunfei, Zhao Wenyan, Geng Donghua, Jin Yuzi, Guan Wenzheng
Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
Department of Pediatrics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110020, China.
J Exp Clin Cancer Res. 2025 Aug 22;44(1):249. doi: 10.1186/s13046-025-03520-6.
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway senses cytosolic DNA and triggers innate immune responses. Pharmacological activation of the cGAS-STING pathway by cGAS-STING agonists to overcome cancer drug resistance offers substantial potential to promote antitumor immunity. However, small-molecule STING agonists show rapid excretion, low bioavailability, non-specificity, and adverse effects, which limit their therapeutic efficacy and in vivo applications. The recent emergence of nanomedicine has profoundly revolutionized STING agonist delivery, promoting tumor-targeted delivery and offering new opportunities for tumor-specific immunotherapy. A growing body of evidence has shown that cGAS-STING interacts with ferroptosis in cancer cells. Targeting the interplay between cGAS-STING and ferroptosis using nanomedicines offers a novel cancer treatment regimen. In this review, we outline the principal components of the cGAS-STING signaling cascade and discuss its role in cancer biology. We also review the role of the interplay between cGAS-STING and ferroptosis in cancer genesis. We then focus on providing an overview of the latest findings and emerging concepts that leverage the interplay between cGAS-STING and ferroptosis by nanomedicine to kill cancers. Finally, we discuss the key limitations of the current therapeutic paradigm and possible strategies to overcome them. This article highlights some promising therapeutic avenues that leverage the interplay of cGAS-STING and ferroptosis by nanomedicine, which could be used to treat cancer.
环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）通路可感知胞质DNA并触发先天性免疫反应。通过cGAS-STING激动剂对cGAS-STING通路进行药理学激活以克服癌症耐药性，为促进抗肿瘤免疫提供了巨大潜力。然而，小分子STING激动剂显示出快速排泄、低生物利用度、非特异性和不良反应，这限制了它们的治疗效果和体内应用。纳米医学的最新出现深刻地革新了STING激动剂的递送方式，促进了肿瘤靶向递送，并为肿瘤特异性免疫治疗提供了新机会。越来越多的证据表明，cGAS-STING在癌细胞中与铁死亡相互作用。利用纳米药物靶向cGAS-STING与铁死亡之间的相互作用提供了一种新的癌症治疗方案。在这篇综述中，我们概述了cGAS-STING信号级联的主要成分，并讨论了其在癌症生物学中的作用。我们还综述了cGAS-STING与铁死亡之间的相互作用在癌症发生中的作用。然后，我们重点概述了利用纳米药物通过cGAS-STING与铁死亡之间的相互作用来杀死癌症的最新发现和新兴概念。最后，我们讨论了当前治疗模式的关键局限性以及克服这些局限性的可能策略。本文强调了一些利用纳米药物通过cGAS-STING与铁死亡之间的相互作用来治疗癌症的有前景的治疗途径。
