Resistance Mechanisms to Anti-PD Cancer Immunotherapy
Abstract
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.
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CD4+ Treg cells suppress immune cells involved in tumor control and are linked to resistance in immunotherapies.
“CD4+ Treg cells, which suppress immune cells involved in tumor control, are linked to resistance in immunotherapies.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [43]
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- Authors
- Vesely, M. D., Zhang, T., & Chen, L.
- Affiliations
- Yale University (US)
- Venue
- Annual Review of Immunology
- Publisher
- Annual Reviews
- Published
- 2022-04-26
- Volume
- 40
- Issue
- 1
- Pages
- 45-74
- ISSN
- 0732-0582 (ISSN-L)
- 1545-3278
- OpenAlex
- W4224982677
- Cited by
- 468
- References
- 64
- Citations by year
- 2026: 96 · 2025: 130 · 2024: 144 · 2023: 80 · 2022: 17
- FWCI
- 11.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (KL2TR001862)
- National Cancer Institute (P50CA196530)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- anti-PD-1 resistance, PD-1/PD-L1 pathway, cancer immunotherapy, tumor microenvironment, interferon signaling, T-cell exclusion, cancer metabolism, gut microbiota, epigenetics, combination immunotherapy
- MeSH terms
- Animals, Humans, Immunotherapy, Neoplasms, T-Lymphocytes, Tumor Microenvironment, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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