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

## TL;DR

APOBEC3 enzymes cause mutations in tumors that can both boost and hinder immune responses, affecting cancer progression and treatment outcomes.

## Contribution

This review explores how APOBEC3-mediated mutagenesis connects genomic instability to immune checkpoint interactions in solid tumors.

## Key findings

- APOBEC3-induced mutations increase tumor mutational burden and neoantigen production, enhancing CD8+ T-cell infiltration.
- Sustained APOBEC3 activity can promote immunosuppression via PD-1/PD-L1 signaling and T-cell dysfunction.
- APOBEC3s act as a mechanistic link between genomic instability and tumor-immune crosstalk in solid cancers.

## Abstract

The apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family was first defined as an innate antiviral defense system, but the APOBEC3 subfamily (APOBEC3s) is now recognized as a major endogenous source of somatic mutagenesis in cancer. APOBEC3s enzymes, particularly APOBEC3A and APOBEC3B, generate characteristic mutation patterns that promote genomic instability, clonal evolution, and adaptation to therapy. Beyond driving tumor evolution, APOBEC3 activity reshapes antitumor immunity in solid cancers. APOBEC3-induced mutations increase tumor mutational burden and create neoantigens that can enhance CD8+ T-cell infiltration and interferon signaling. However, sustained APOBEC activation may also reinforce immunosuppressive circuits: through chronic inflammation and PD-1/PD-L1–interferon signaling, tumors can induce T-cell dysfunction, immune escape, and resistance to immune checkpoint blockade. This functional ambivalence has sparked debate over whether APOBEC3s should be inhibited to limit genomic instability, leveraged to enhance tumor immunogenicity, or modulated dynamically in a context-dependent manner. This review outlines the immune landscape and biochemical characteristics of the APOBEC3 family and situates these features within broader cancer-related disease contexts. APOBEC3-mediated mutagenesis is discussed as a mechanistic link between genomic instability and tumor–immune crosstalk in solid tumors, with emphasis on its relationships to immunoediting, immune checkpoint pathways, and therapeutic responses. Context-dependent associations of APOBEC3 activity with immune activation or immune evasion are also considered, together with their implications for strategies that modulate this pathway.

Infographic illustrating APOBEC3s activity across biological scales, showing population-level variation in APOBEC activity, chemical conversion of cytosine to uracil, its role in remodeling tumor cell programs, neoantigen creation, and translational applications in research, therapeutics, and engineering.