Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy
Open accessAbstract
Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.
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The majority of patients do not respond to checkpoint therapies as a result of heightened immunosuppression in the tumor microenvironment or inadequate non-self antigenic load within the tumor.
“the majority of patients do not respond as a result of heightened immunosuppression in the tumor microenvironment or inadequate non-self antigenic load within the tumor”
From LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer (2018) · cites this paper as Sharma et al., 2017
The Introduction (p. 4) says most patients do not benefit from immunotherapy. The sections on primary and adaptive resistance (pp. 4, 6) identify absent tumor antigens and immunosuppressive components of the tumor microenvironment as causes of resistance. The paper does not establish that these two mechanisms account for nonresponse in the majority of patients; it describes other mechanisms as well. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOvercoming resistance to cancer immunotherapy remains a central challenge.
“Cancer immunotherapy with immune checkpoint blockade (ICB) has transformed the treatment of advanced melanoma and other cancers, although overcoming resistance remains a central challenge 1,2 .”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [2]
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 [42]
The tumor microenvironment is a complex ecosystem comprised of multiple cell types that support the growth of tumor cells, facilitate tumor progression, and modulate therapeutic response to anti-cancer treatments.
“The tumor microenvironment is a complex ecosystem comprised of multiple cell types that support the growth of tumor cells, facilitate tumor progression, and modulate therapeutic response to anti-cancer treatments [29,99,100,120,121].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [29]
CtDNA levels correlate strongly with tumor burden and progression.
“CtDNA levels correlate strongly with tumor burden and progression (105, 106).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [105]
IDO inhibits T cell function.
“The tryptophan-metabolizing enzyme IDO inhibits T cell function, and combining IDO-blocking agents together with immune checkpoint inhibitors has shown promising results in mice and is also currently undergoing clinical trials in humans (105, 118).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [105]
Combining IDO-blocking agents with immune checkpoint inhibitors has shown promising results in mice.
“The tryptophan-metabolizing enzyme IDO inhibits T cell function, and combining IDO-blocking agents together with immune checkpoint inhibitors has shown promising results in mice and is also currently undergoing clinical trials in humans (105, 118).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [105]
Response markers for cancer therapy now include factors beyond tumor-centric markers, such as overall immune status and tumor microenvironment components.
“markers of response to cancer therapy have continued to evolve and now include factors well beyond established tumor-centric markers”
From The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy (2018) · cites this paper as Sharma et al., 2017
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- Authors
- Sharma, P., Hu-Lieskovan, S., Wargo, J. A., & Ribas, A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of California, Los Angeles (US)
- Corresponding author
- Sharma, Padmanee
- Ribas, Antoni
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 168
- Issue
- 4
- Pages
- 707-723
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5391692
- OpenAlex
- W2587048937
- Cited by
- 5,588
- References
- 187
- Citations by year
- 2026: 634 · 2025: 679 · 2024: 732 · 2023: 731 · 2022: 704 · 2021: 685 · 2020: 578 · 2019: 421 · 2018: 322 · 2017: 99 · 2015: 1
- FWCI
- 41.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH/NCI (R01 CA1633793, R35 CA197633, P01 CA168585)
- Cancer Prevention Research in Texas (RP120108)
- Cancer-Cancer Research Institute Cancer Immunology Dream Team Translational Research (SU2C-AACR-DT1012)
- 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
- cancer immunotherapy, immunotherapy resistance, primary resistance, adaptive resistance, acquired resistance, immune evasion, tumor immune microenvironment, metastatic cancer, immune checkpoint inhibitors
- MeSH terms
- Animals, Drug Therapy, Combination, Humans, Immunotherapy, Neoplasms, T-Lymphocytes, Molecular Targeted Therapy
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