Resistance Mechanisms to Anti-PD Cancer Immunotherapy

Annu Rev Immunol. 2022 Apr 26;40:45-74. doi: 10.1146/annurev-immunol-070621-030155.


The transformative success of antibodies targeting the PD-1 (programmed death 1)/B7-H1 (B7 homolog 1) pathway (anti-PD therapy) has revolutionized cancer treatment. However, only a fraction of patients with solid tumors and some hematopoietic malignancies respond to anti-PD therapy, and the reason for failure in other patients is less known. By dissecting the mechanisms underlying this resistance, current studies reveal that the tumor microenvironment is a major location for resistance to occur. Furthermore, the resistance mechanisms appear to be highly heterogeneous. Here, we discuss recent human cancer data identifying mechanisms of resistance to anti-PD therapy. We review evidence for immune-based resistance mechanisms such as loss of neoantigens, defects in antigen presentation and interferon signaling, immune inhibitory molecules, and exclusion of T cells. We also review the clinical evidence for emerging mechanisms of resistance to anti-PD therapy, such as alterations in metabolism, microbiota, and epigenetics. Finally, we discuss strategies to overcome anti-PD therapy resistance and emphasize the need to develop additional immunotherapies based on the concept of normalization cancer immunotherapy.

Keywords: PD-1/B7-H1; anti-PD-1/PD-L1 therapy; immunotherapy resistance; normalization cancer immunotherapy.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B7-H1 Antigen
  • Humans
  • Immunotherapy
  • Neoplasms* / drug therapy
  • Neoplasms* / metabolism
  • Programmed Cell Death 1 Receptor*
  • T-Lymphocytes
  • Tumor Microenvironment


  • B7-H1 Antigen
  • Programmed Cell Death 1 Receptor