Targeting the interplay of cGAS-STING and ferroptosis by nanomedicine in the treatment of cancer

Sep 23, 2026

Uploaded by McQueen

The cyclic GMP–AMP synthase (cGAS)–STING pathway detects cytosolic DNA and drives innate immune activation, and pharmacologic cGAS-STING agonism is explored to promote antitumor immunity while overcoming drug resistance. Small-molecule STING agonists are limited by rapid excretion, low bioavailability, nonspecificity, and adverse effects. Nanomedicine is presented as a delivery platform enabling tumor-targeted administration, improving therapeutic opportunities. Evidence links cGAS-STING signaling with ferroptosis, motivating nanomedicine-based strategies that couple the pathway to ferroptotic cell death. This review summarizes cGAS-STING components, discusses roles in cancer biology and genesis, reviews latest findings and emerging concepts, and addresses current limitations and mitigation approaches for more effective cancer treatment.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages39

Reading Time1 h 38 min

AccessFree to download

Abstract

Introduction

Cancer metastasis and immunotherapy limitations

cGAS-STING pathway in tumor regulation

Therapeutic targeting constraints and delivery needs

Keywords

Li etal. Journal of Experimental & Clinical Cancer Research (2025) 44:249 [https://doi.org/10.1186/s13046-025-03520-6](https://doi.org/10.1186/s13046-025-03520-6) Journal of Experimental & Clinical Cancer Research REVIEW Open Access Targeting the interplay of cGAS-STING and ferroptosis by nanomedicine in the treatment of cancer Chunfei Li 1†, Wenyan Zhao 1†, Donghua Geng 1, Yuzi Jin2 and Wenzheng Guan3* Abstract 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 agoniststo overcome cancer drug resistance offers substantial potential to promote antitumor immunity. However, smallmolecule 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 ferroptosisin 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. Keywords Cancer, cGAS-STING, Ferroptosis, Nanomedicine †Chunfei Li and Wenyan Zhao contributed equally to this work. *Correspondence: Wenzheng Guan [cmuwzguan@163.com](cmuwzguan@163.com) 1Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China 2Department of Pediatrics, Central Hospital Affiliated to Shenyang Medical College, Shenyang 110020, China 3Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China Introduction Cancer metastasis refers to the growth and colonization of cancer cells in organs distant from the organ of origin. Metastasis, which characterizes a malignant tumor and distinguishes it from a benign tumor, is a hallmark of cancer associated with invasiveness [1, 2]. Metastasis is the ultimate and most lethal manifestation of cancer, leading to the vast majority (90%) of cancer deaths [3–6]. Immunotherapeutic agents such as anti-programmed death-ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors have emerged as revolutionary cancer treatments [7]. However, their low response rates, resistance, and toxicity pose © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright h

FAQs

What does the cGAS-STING pathway detect and what is its immune role?

It senses cytosolic DNA and triggers innate immune responses, promoting antitumor immunity through downstream signaling.

Why are small-molecule STING agonists difficult to use clinically?

They are constrained by rapid excretion, low bioavailability, nonspecificity, and adverse effects that reduce in vivo efficacy and limit application.

How does nanomedicine change the delivery of STING agonists?

Nanomedicine improves delivery by enabling tumor-targeted administration and offering new opportunities for tumor-specific immunotherapy.

Sep 23, 2026

Uploaded by McQueen