Overcoming acquired resistance to cancer immune checkpoint therapy: potential strategies based on molecular mechanisms

Bin Wang; Yin Han; Yuyu Zhang; Qin Zhao; Huanhuan Wang; Jinlong Wei; Lingbin Meng; Ying Xin; Xin Jiang

doi:10.1186/s13578-023-01073-9

Overcoming acquired resistance to cancer immune checkpoint therapy: potential strategies based on molecular mechanisms

Cell Biosci. 2023 Jun 30;13(1):120. doi: 10.1186/s13578-023-01073-9.

Authors

Bin Wang^#^{1

2}, Yin Han^#³, Yuyu Zhang^{1

4

5}, Qin Zhao^{1

2

3}, Huanhuan Wang^{1

4

5}, Jinlong Wei^{1

4

5}, Lingbin Meng⁶, Ying Xin⁷, Xin Jiang^{8

9

10}

Affiliations

¹ Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China.
² Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
³ Cancer Prevention and Treatment Institute of Chengdu, Department of Pathology, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, 611137, China.
⁴ Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, 130021, China.
⁵ NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China.
⁶ Department of Hematology and Medical Oncology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
⁷ Key Laboratory of Pathobiology, Ministry of Education, Jilin University, 126 Xinmin Street, Changchun, 130021, China. xiny@jlu.edu.cn.
⁸ Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China. jiangx@jlu.edu.cn.
⁹ Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, 130021, China. jiangx@jlu.edu.cn.
¹⁰ NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, China. jiangx@jlu.edu.cn.

^# Contributed equally.

Abstract

Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1/PD-L1 to boost tumor-specific T lymphocyte immunity have opened up new avenues for the treatment of various histological types of malignancies, with the possibility of durable responses and improved survival. However, the development of acquired resistance to ICI therapy over time after an initial response remains a major obstacle in cancer therapeutics. The potential mechanisms of acquired resistance to ICI therapy are still ambiguous. In this review, we focused on the current understanding of the mechanisms of acquired resistance to ICIs, including the lack of neoantigens and effective antigen presentation, mutations of IFN-γ/JAK signaling, and activation of alternate inhibitory immune checkpoints, immunosuppressive tumor microenvironment, epigenetic modification, and dysbiosis of the gut microbiome. Further, based on these mechanisms, potential therapeutic strategies to reverse the resistance to ICIs, which could provide clinical benefits to cancer patients, are also briefly discussed.

Keywords: Acquired resistance; Combination therapy; Immune checkpoint inhibitors; Mechanisms; Tumor microenvironment.

Publication types

Review

Abstract

Publication types

Grants and funding