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Wong et al. Cancer Drug Resist 2023;6:768-87 Cancer
DOI: 10.20517/cdr.2023.58
Drug Resistance

Review Open Access

Immune checkpoint inhibitors in breast cancer:
development, mechanisms of resistance and

potential management strategies

1,2
2
Rachel SJ Wong , Rebecca JM Ong , Joline SJ Lim 1,2
1
Department of Haematology-Oncology, National University Cancer Institute, National University Hospital, Singapore 119228,
Singapore.
2
Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
Correspondence to: Dr. Joline SJ Lim, Department of Haematology-Oncology, National University Cancer Institute, National
University Hospital, 1E Kent Ridge Road, Singapore 119228, Singapore. E-mail: csilsjj@nus.edu.sg

How to cite this article: Wong RSJ, Ong RJM, Lim JSJ. Immune checkpoint inhibitors in breast cancer: development, mechanisms of
resistance and potential management strategies. Cancer Drug Resist 2023;6:768-87. https://dx.doi.org/10.20517/cdr.2023.58
Received: 11 Jun 2023 First Decision: 13 Sep 2023 Revised: 14 Oct 2023 Accepted: 31 Oct 2023 Published: 17 Nov 2023

Academic Editor: Godefridus J. Peters Copy Editor: Pei-Yun Wang Production Editor: Pei-Yun Wang

Abstract
The use of immune checkpoint inhibitors (ICIs) has increased exponentially in the past decade, although its
progress specifically for breast cancer has been modest. The first U.S. Food and Drug Administration approval for
ICI in breast cancer came in 2019, eight years after the first-ever approval of an ICI. At present, current indications
for ICIs are relevant only to a subset of patients with triple-negative breast cancer, or those displaying high
microsatellite instability or deficiency in the mismatch repair protein pathway. With an increasing understanding of
the limitations of using ICIs, which stem from breast cancer being innately poorly immunogenic, as well as the
presence of various intrinsic and acquired resistance pathways, ongoing trials are evaluating different combination
therapies to overcome these barriers. In this review, we aim to describe the development timeline of ICIs and
resistance mechanisms limiting their utility, and summarise the available approaches and ongoing trials relevant to
overcoming each resistance mechanism.

Keywords: Immunotherapy, immune checkpoint inhibitors, resistance mechanisms, breast cancer

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
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