Review Volume 14, Issue 2 pp 1048—1064

Acquired resistance for immune checkpoint inhibitors in cancer immunotherapy: challenges and prospects

Xunrui Chen1, *, , Wenhui Zhang2, *, , Wenyan Yang3, , Min Zhou4, &, , Feng Liu1, ,

  • 1 Department of Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201900, China
  • 2 Shanghai Institute of Precision Medicine, Shanghai 200125, China
  • 3 Medical Center, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China
  • 4 Department of Respirtory Medicine, Jinshan Branch of the Sixth People’s Hospital of Shanghai, Shanghai 201599, P.R. China
* Equal contribution as co-first author

Received: July 19, 2021       Accepted: December 29, 2021       Published: January 17, 2022
How to Cite

Copyright: © 2022 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Drug resistance has become an obstacle to the further development of immunotherapy in clinical applications and experimental studies. In the current review, the acquired resistance to immunotherapy was examined. The mechanisms of acquired resistance were based on three aspects as follows: The change of the tumor functions, the upregulated expression of inhibitory immune checkpoint proteins, and the effects of the tumor microenvironment. The combined use of immunotherapy and other therapies is performed to delay acquired resistance. A comprehensive understanding of acquired drug resistance may provide ideas for solving this dilemma.


CAFs: Cancer-associated fibrous cells; DCs: Dendritic cells; ECM: Extracellular matrix; FDA: Food and Drug Administration; HLA: Human leukocyte antigen; ICIs: Immune checkpoint inhibitors; IDO: Indoleamine 2,3-dioxygenase; iNOS: Inducible Nitric oxide synthase; MDSCs: Myeloid-derived suppressor cells; MMP: Matrix metalloproteinases; MSI/dMMR: Microsatellite instability/defective mismatch repair; NSCLC: Non-small cell lung cancer; PFS: Progression-free survival; RCC: Renal cell carcinoma; RT: Radiotherapy; TADCs: Tumor-associated dendritic cells; TAEs: Tumor-associated endothelial cells; TAMCs: Tumor-associated mast cells,; TAMs: Tumor-associated macrophages; Teff: effector T cells; TGF-β: Transforming growth factor β; TME: Tumor microenvironment; Treg: Regulatory T cells; β-2M: beta-2-microglobulin.