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Jun 11, 2025;24 (1): 176.

Enhancing radiotherapy-induced anti-tumor immunity via nanoparticle-mediated STING agonist synergy.

Qian Zeng, Min Liu, Ziqi Wang, Rongrong Zhou, Kelong Ai
Author Information
  1. Qian Zeng: Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
  2. Min Liu: Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China.
  3. Ziqi Wang: Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
  4. Rongrong Zhou: Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China. zhourr@csu.edu.cn.
  5. Kelong Ai: Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China. aikelong@csu.edu.cn.
PMID: 40500702 DOI: 10.1186/s12943-025-02366-y

Abstract

Radiotherapy (RT) remains a cornerstone treatment for over 50% of cancer patients, primarily via ionizing radiation-induced DNA damage to exert therapeutic effects. Notably, emerging studies have revealed its additional capacity to activate systemic anti-tumor immune responses through inducing immunogenic cell death (ICD) and activating the cGAS-STING pathway, further expanding its therapeutic potential. However, its efficacy is often limited by immunosuppressive tumor microenvironment (TME). Additionally, while RT can activate the cGAS-STING pathway, this activation remains transient and suboptimal, failing to sustain robust anti-tumor immunity. Therefore, combining RT with STING agonists may benefit traditional therapy by amplifing tumor immunogenicity and counteracting immune evasion. Despite promising results, challenges such as off-target toxicity, poor cell membrane permeability and poor bioavailability, remain obstacles to clinical translation of conventional STING agonists. Nanomedicine offers a promising approach by enabling targeted delivery of STING agonists and amplifying RT-induced DNA damage through nanoscale radiosensitizers. In this review, we provide a detailed discussion of the immune-stimulatory and immune-suppressive effects of RT, as well as the mechanisms and biological effects of selectively activating the cGAS-STING pathway in key TME components. On this basis, we further explore recent advancements in nano-STING agonists-mediated anti-tumor immunity in synergy with RT. This combinatorial approach achieves dual radiosensitization and immunostimulation, ultimately driving immune memory formation and TME reprogramming. Finally, the application prospects and challenges of nano-STING agonists-based immunotherapy are also discussed from the perspective of clinical translation.

Keywords

CGAS–STING signaling Cancer Nanoparticle Radiotherapy Target

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Grants

  1. 82373871/National Natural Science Foundation of China

MeSH Term

Humans
Membrane Proteins
Neoplasms
Animals
Nanoparticles
Tumor Microenvironment
Signal Transduction
Radiation-Sensitizing Agents

Chemicals

Membrane Proteins
STING1 protein, human
Radiation-Sensitizing Agents
Journal Article Review

Word Cloud

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