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Targeted degradation of immune checkpoint proteins: emerging strategies for cancer immunotherapy

Oncogene volume 39, pages 7106–7113 (2020)Cite this article

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Abstract

Cancer immunotherapy using immune-checkpoint blockade has displayed promising clinical effects, but prevalent antibody-based inhibitors face multiple challenges such as low response rate, acquired resistance, and adverse effects. The intracellular expression of PD-1/PD-L1 in recycling endosomes and their active trafficking to membrane highlight the importance of depleting rather than interfering with checkpoint proteins. Preclinical investigations on the therapeutic effects of lead compounds that function by degrading immune checkpoint ligands and receptors have reported highly promising results. By harnessing the degradation capabilities of the lysosome, proteasome and autophagosomes, different small molecules and peptides potently induced degradation of checkpoint proteins and enhanced anti-tumor immunity. Both in vitro and in vivo experiments support the therapeutic efficacy of these molecules. Thus, targeted degradation through endo-lysosomal, autophagic, proteasomal, or endoplasmic reticulum-related pathways may provide promising strategies for tackling the challenges in cancer immunotherapy.

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Fig. 1: Modes of actions of different targeting molecules.
Fig. 2: Repurposed screening as a promising strategy for discovering immune checkpoint inhibitors.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (No: 82030104, 81874050, 81572326), Basic Research Projects of Shanghai Science and Technology Innovation Action Plan (20JC1410700); National Key R & D Program of China (2016YFC0906002, 2016YFC0906002), Tang Scholar (JX), and Startup Research Funding of Fudan University.

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Authors and Affiliations

  1. Institutes of Biomedical Sciences and Zhongshan-Xuhui Hospital, Key Laboratory of Epigenetics and Metabolism, Fudan University, Shanghai, China

    Jie Xu

  2. Centre de Recherche du Centre Hospitalier de Sherbrooke, Sherbrooke, Canada

    Jean-Philippe Brosseau

  3. Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Canada

    Jean-Philippe Brosseau

  4. Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China

    Hubing Shi

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Correspondence to Jie Xu.

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Xu, J., Brosseau, JP. & Shi, H. Targeted degradation of immune checkpoint proteins: emerging strategies for cancer immunotherapy. Oncogene 39, 7106–7113 (2020). https://doi.org/10.1038/s41388-020-01491-w

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