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Chemotherapy-induced CA-repeat DNA fragments in breast cancer trigger antitumor immune responses

Xiaoqian Zhang1,2, Penghan Huang1,2, Huiping Chen1,2

  • 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

Nature Immunology
|September 30, 2025
PubMed

Insights

Cancer chemotherapy generates DNA fragments that trigger distinct immune responses. Cytosine-adenine (CA)-rich DNA fragments promote antitumor immunity, while CA-poor DNA fragments cause immunosuppression, offering therapeutic potential.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Damage-associated molecular patterns (DAMPs) from cancer treatment influence antitumor immunity, but mechanisms are poorly understood.
  • The role of specific DNA fragment characteristics in immune modulation requires further elucidation.

Purpose of the Study:

  • To investigate how chemotherapy-induced DNA fragments modulate antitumor immunity.
  • To explore the differential immune effects of cytosine-adenine (CA)-rich versus CA-poor DNA fragments.
  • To assess the therapeutic potential of CA-rich DNA fragments in enhancing antitumor immunity.

Main Methods:

  • Analysis of DNA fragment binding to cGAS and AIM2 sensors.
  • Investigation of biomolecular condensate formation and immune signaling pathways.
  • In vivo studies using syngrafted PyMT tumors and intratumoral administration of DNA fragments.
  • Clinical correlation analysis of CA-rich DNA abundance with immune cell populations and treatment response in breast cancer patients.

Main Results:

  • CA-enriched DNA fragments from MSH2-low tumors bind cGAS, forming condensates and promoting antitumor immunity.
  • CA-poor DNA fragments from MSH2-high tumors engage AIM2, leading to immunosuppression via PD-L1 and IDO upregulation.
  • Intratumoral administration of CA-rich DNA enhanced immunity in PyMT tumors.
  • Clinically, higher CA-rich DNA levels in breast cancer correlated with increased tumor-antigen-reactive T cells and improved chemotherapy response.

Conclusions:

  • Tumor DNA fragments with varying CA content trigger opposing immune responses by differential sensor engagement (cGAS vs. AIM2).
  • CA-rich DNA fragments represent a promising therapeutic strategy to enhance antitumor immunity and improve chemotherapy efficacy.
  • This study reveals a novel link between genome instability, DNA sensing, and immune modulation in cancer treatment.

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