Targeting EZH2 to mitigate immune checkpoint resistance in ARID1A-deficient triple-negative breast cancer

Abstract

Immune checkpoint inhibitors (ICIs) have shown promise in treating triplenegative breast cancer (TNBC), but resistance to these therapies remains a significant challenge. AT-rich interactive domain 1A (ARID1A), a component of the SWItch/Sucrose Non-Fermentable chromatin remodeling complex, is frequently mutated in TNBC and is associated with increased programmed cell death ligand 1 expression, which contributes to immune evasion. Paradoxically, this mutation may make TNBC potentially more responsive to ICIs. Chromatin-mediated gene expression requires a balance between ARID1A and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, and ARID1A deficiency results in enhanced EZH2 activity, contributing to various oncologic processes. Epigenetic modulation through EZH2 inhibition could exploit the synthetic lethality between ARID1A deficiency and EZH2 activity, which may reduce the immunosuppressive tumor microenvironment and enhance infiltration and activity of cytotoxic T-cells within the tumor, thereby synergizing with immune checkpoint inhibition. This review explores the potential of EZH2 inhibition as a therapeutic strategy to overcome immune checkpoint resistance in ARID1A-deficient TNBC. In addition, the role of ARID1A deficiency as a radiosensitizer is also discussed in the context of combination therapy strategies.

Keywords

Epigenetic / Immunotherapy / Triple-negative breast cancer / Combination therapy / Radiotherapy

Acknowledgments

Figures created in BioRender.com by Evelina VanderSpek and Lauren Lukas.

Funding

None.

Conflict of Interest

The authors declare they have no competing interests.

Author contributions

Conceptualization: Lauren Lukas

Visualization: Lauren Lukas

Writing - original draft: Lauren Lukas

Writing - review & editing: All authors

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data

Not applicable.

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