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Reprogramming tumor immunity through APOBEC3s-mediated mutagenesis: from genome instability to immune checkpoint

Qiaoxi Li1,2, Wenyu Wan1,2, Zihan Zhu1,2

  • 1Department of Dermatology, The First Hospital of China Medical University, Shenyang, China.

Frontiers in Immunology
|February 27, 2026
PubMed

Insights

The apolipoprotein B mRNA editing catalytic polypeptide-like 3 (APOBEC3) subfamily drives cancer mutations and genomic instability. APOBEC3s can enhance anti-tumor immunity or promote immune evasion, depending on the cancer context.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • The apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family, initially known for antiviral defense, is now recognized as a key source of somatic mutations in cancer.
  • The APOBEC3 subfamily (APOBEC3s), particularly APOBEC3A and APOBEC3B, contributes significantly to genomic instability, clonal evolution, and therapeutic adaptation in tumors.

Purpose of the Study:

  • To review the immune landscape and biochemical characteristics of the APOBEC3 family in cancer.
  • To explore the dual role of APOBEC3 activity in shaping antitumor immunity and influencing therapeutic responses.
  • To discuss the implications of APOBEC3-mediated mutagenesis for cancer immunoediting and immune checkpoint pathways.

Main Methods:

  • Literature review and synthesis of existing research on APOBEC3 enzymes in cancer.
  • Analysis of the impact of APOBEC3-induced mutations on tumor mutational burden and neoantigen formation.
  • Examination of the relationship between APOBEC3 activity, immune signaling, and immune evasion in solid tumors.

Main Results:

  • APOBEC3s promote genomic instability and can enhance anti-tumor immunity by increasing neoantigens and T-cell infiltration.
  • Sustained APOBEC3 activation can also lead to immune suppression through chronic inflammation and PD-1/PD-L1 signaling, causing T-cell dysfunction and resistance to immunotherapy.
  • The net effect of APOBEC3 activity on antitumor immunity is context-dependent, influencing immunoediting and therapeutic outcomes.

Conclusions:

  • APOBEC3-mediated mutagenesis serves as a critical link between genomic instability and tumor-immune crosstalk in solid tumors.
  • Modulating APOBEC3 activity presents a potential therapeutic strategy, but requires a context-dependent approach due to its dual role in immunity.
  • Understanding the intricate relationship between APOBEC3s, genomic instability, and the tumor immune microenvironment is crucial for developing effective cancer treatments.
Keywords:
APOBEC3 cytidine deaminasesgenomic instability and DNA repairimmune checkpoint blockademutational signaturesneoantigens and immunotherapy resistanceprecision immuno-oncologytumor immune microenvironmenttumor immunoediting

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