Page 36 - ARNM-3-1

Advances in Radiotherapy &

Nuclear Medicine

REVIEW ARTICLE
Targeting EZH2 to mitigate immune checkpoint

resistance in ARID1A-deficient triple-negative
breast cancer

Lauren Lukas * , Hye Ri Han , Evanthia T. Roussos Torres , Aaron G. Baugh ,
1
1
2
2
Oliver Bell , Jason C. Ye , Kenneth Wong , Vyshnavi Pachipulusu ,
3
4
1
1
Hualin Zhang , and Alan L. Epstein 4
1
1 Department of Radiation Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine,
University of Southern California, Los Angeles, California, United States of America
2 Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck
School of Medicine, University of Southern California, Los Angeles, California, United States of
America
3 Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of
Southern California, Los Angeles, California, United States of America
4 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles,
California, United States of America
(This article belongs to the Special Issue: Novel developments in cancer therapy utilizing
combinatorial approaches of radiotherapy and immunotherapy)
*Corresponding author:
Lauren Lukas
(llukas@usc.edu)
Citation: Lukas L, Han HR, Abstract
Torres ETR, et al. Targeting EZH2
to mitigate immune checkpoint
resistance in ARID1A-deficient Immune checkpoint inhibitors (ICIs) have shown promise in treating triple-
triple-negative breast cancer. negative breast cancer (TNBC), but resistance to these therapies remains a
Adv Radiother Nucl Med. significant challenge. AT-rich interactive domain 1A (ARID1A), a component of the
2025;3(1):28-45.
doi: 10.36922/arnm.5132 SWItch/Sucrose Non-Fermentable chromatin remodeling complex, is frequently
mutated in TNBC and is associated with increased programmed cell death ligand
Received: October 13, 2024
1 expression, which contributes to immune evasion. Paradoxically, this mutation
1st revised: December 11, 2024 may make TNBC potentially more responsive to ICIs. Chromatin-mediated gene
2nd revised: December 24, 2024 expression requires a balance between ARID1A and enhancer of zeste homolog
2 (EZH2), a histone methyltransferase, and ARID1A deficiency results in enhanced
Accepted: December 25, 2024
EZH2 activity, contributing to various oncologic processes. Epigenetic modulation
Published online: January 16, through EZH2 inhibition could exploit the synthetic lethality between ARID1A
2025 deficiency and EZH2 activity, which may reduce the immunosuppressive tumor
Copyright: © 2025 Author(s). microenvironment and enhance infiltration and activity of cytotoxic T-cells within
This is an Open-Access article the tumor, thereby synergizing with immune checkpoint inhibition. This review
distributed under the terms of the
Creative Commons Attribution explores the potential of EZH2 inhibition as a therapeutic strategy to overcome
License, permitting distribution, immune checkpoint resistance in ARID1A-deficient TNBC. In addition, the role
and reproduction in any medium, of ARID1A deficiency as a radiosensitizer is also discussed in the context of
provided the original work is
properly cited. combination therapy strategies.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: Epigenetic; Immunotherapy; Triple-negative breast cancer; Combination
regard to jurisdictional claims in
published maps and institutional therapy; Radiotherapy
affiliations

Volume 3 Issue 1 (2025) 28 doi: 10.36922/arnm.5132