Mechanisms of Resistance to Checkpoint Blockade Therapy

  • Hubing ShiEmail author
  • Jiang Lan
  • Jiqiao Yang
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1248)


Immune checkpoint blockades (ICBs), as a major breakthrough in cancer immunotherapy, target CTLA-4 and the PD-1/PD-L1 axis and reinvigorate anti-tumor activities by disrupting co-inhibitory T-cell signaling. With unprecedented performance in clinical trials, ICBs have been approved by FDA for the treatment of malignancies such as melanoma, non-small-cell lung cancer, colorectal cancer, and hepatocellular carcinoma. However, while ICBs are revolutionizing therapeutic algorithms for cancers, the frequently observed innate, adaptive or acquired drug resistance remains an inevitable obstacle to a durable antitumor activity, thus leading to non-response or tumor relapse. Researches have shown that resistance could occur at each stage of the tumor’s immune responses. From the current understanding, the molecular mechanisms for the resistance of ICB can be categorized into the following aspects: 1. Tumor-derived mechanism, 2. T cell-based mechanism, and 3. Tumor microenvironment-determined resistance. In order to overcome resistance, potential therapeutic strategies include enhancing antigen procession and presentation, reinforcing the activity and infiltration of T cells, and destroying immunosuppression microenvironment. In future, determining the driving factors behind ICB resistance by tools of precision medicine may maximize clinical benefits from ICBs. Moreover, efforts in individualized dosing, intermittent administration and/or combinatory regimens have opened new directions for overcoming ICB resistance.


PD-1 PD-L1 CTLA-4 Resistance Precision medicine 


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© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.The State Key Laboratory of BiotherapySichuan University West China HospitalChengduChina

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