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Updated: Aug 18, 2026

Quantitative Detection of DNA-Protein Crosslinks and Their Post-Translational Modifications
10:12

Quantitative Detection of DNA-Protein Crosslinks and Their Post-Translational Modifications

Published on: April 21, 2023

The Dual Role of DNA Cross-linking Agents: From Genotoxicity to cGAS-STING-Mediated Immune Activation

Jingao Li1, Luo Wang1, Xuqing Mao1

  • 1State Key Laboratory of Experimental Hematology; The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin300070, China.

Chemical Research in Toxicology
|August 17, 2026
PubMed

Insights

DNA cross-linking agents in cancer therapy activate innate immunity by generating DNA fragments that trigger the cGAS-STING pathway. This immune response, akin to an in situ vaccine, enhances antitumor activity.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • DNA cross-linking agents are vital cancer chemotherapeutics, traditionally viewed as direct cytotoxins.
  • Emerging evidence reveals their role in activating innate immune responses.
  • DNA damage response pathways can lead to cytosolic DNA fragment generation.

Purpose of the Study:

  • To review the molecular mechanisms linking DNA cross-linking agents to innate immune activation.
  • To explore the role of the cGAS-STING pathway in mediating antitumor immunity.
  • To discuss therapeutic strategies combining DNA cross-linking agents with immune-activating therapies.

Main Methods:

  • Review of existing literature on DNA cross-linking agents, DNA damage response, and cGAS-STING signaling.
  • Summarization of the chemistry and replication stress induced by these agents.
  • Analysis of mechanisms driving cytosolic DNA generation and immune stimulation.

Main Results:

  • DNA cross-linking agents induce replication stress and DNA damage, leading to aberrant repair and cytosolic DNA fragments.
  • These fragments activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.
  • Activation of cGAS-STING drives type I interferon and cytokine production, promoting antitumor immunity.

Conclusions:

  • DNA cross-linking agents function not only as cytotoxins but also as in situ vaccines by harnessing DNA damage-induced immunity.
  • Combining these agents with STING agonists offers a promising strategy for enhanced cancer immunotherapy.
  • Understanding this dual mechanism reframes the therapeutic potential of DNA cross-linking agents.

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