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Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox
Open accessAbstract
Cytotoxic T cells are important effectors of anti-tumor immunity. While tumor killing is ascribed to CD8 + T cell function, pre-clinical and clinical studies have identified intra-tumoral CD4 + T cells that possess cytotoxic programs and can directly kill cancer cells. Cytotoxic CD4 + T cells are found in other disease settings including infection and autoimmunity. Here, we review the phenotypic and functional characteristics of cytotoxic CD4 + T cells in non-cancer and cancer contexts. We conduct a comparative examination of cytolytic mechanisms of cytotoxic CD4 + T cells across disease states and synthesize features that define these cells independent of context. We discuss regulatory mechanisms driving ontogeny and effector function and evidence for the clinical relevance of cytotoxic CD4 + T cells in cancer. In this context, we highlight important gaps in understanding in the biology of cytotoxic CD4 + T cells as well as the potential use of these cells in immunotherapies for specific cancers.
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“we observed a significant increase in the total CD4+ T cells expressing IFN-γ (figure 4H) and granzyme B (GZMB; figure 4J),60–65 NK cells (figure 4N), and the amount of GZMB expression in CD8+ T cells (figure 4L) in the post-cryoablated RMS 76-9STINGwt TME as compared with RMS 76-9STING-/- TME in wild-type mice, as was Foxp3+ CD4+ cells (figure 4M).”
From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [64]
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BackgroundFerguson, A. L., Beddow, T., Patrick, E., Willie, E., Elliott, M., Low, T.-H. H., Wykes, J., Hui, M. H., Palme, C. E., Boyer, M. J., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.18.590189 · Cited by 1
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“Although the reactivation of CD8+ T cell activity has been the major focus of ICI research there is growing evidence that CD4+ T cells may also be critical (27).”
BackgroundPrediction of Efficacy of Immunotherapy for Extensive Stage Small Cell Lung Cancer
斯琴高娃, 李. (2023) · Advances in Clinical Medicine · doi:10.12677/acm.2023.1351193
Fang, C., Liu, J., Xu, L., Lou, W., Wang, Y., & Jiang, T. (2023) · Research Square · doi:10.21203/rs.3.rs-3167884/v1
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RETRACTED: Grain-sized moxibustion enhances anti-tumor immunity of tumor cell lysate vaccinePreprint
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TIM-3 blockade as a therapeutic approach for diffuse intrinsic pontine glioma
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The Science of CAR ‐T Cell Technology
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KNL1 is a lung cancer prognostic biomarker associated with the immune microenvironmentPreprint
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Interleukin-33: A new frontier in cancer immunotherapy
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Single-cell transcriptomics analysis of primary lung adenocarcinoma and lymph node metastatic tumorsPreprint
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DUSP11 is an Intracellular Innate Immune Checkpoint in Lung Adenocarcinoma
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“Recent investigations have shown that cytotoxic CD4 + T cells also possess direct anti-tumor activity against several common tumors (43).”
In vivo vaccine generation with a topical small molecule cocktail to eradicates AML and PDACPreprint
Zheng, S., Li, M., Wu, Z., Zhang, X., Gan, X., & Xu, R. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.19.683274
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T-Cell Responses and T-Cell-Based Therapy in Acute Myeloid Leukemia
Huang, Z., & He, R. (2025) · Current Medical Science · doi:10.1007/s11596-025-00121-4
Metadata
- Authors
- Oh, D. Y., & Fong, L.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Fong, Lawrence
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 54
- Issue
- 12
- Pages
- 2701-2711
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC8809482
- OpenAlex
- W4200244347
- Cited by
- 467
- References
- 73
- Citations by year
- 2026: 81 · 2025: 127 · 2024: 116 · 2023: 101 · 2022: 41 · 2021: 1
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- NCI
- National Institutes of Health (K08AI139375)
- Prostate Cancer Foundation (R35CA253175)
- Bavarian Nordic
- Genentech
- Parker Institute for Cancer Immunotherapy
- AbbVie
- Amgen
- Merck
- Merck KGaA
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- cytotoxic CD4+ T cells, antitumor immunity, cytotoxicity mechanism, cancer immunotherapy, infection, autoimmunity
- MeSH terms
- Animals, Cytotoxicity, Immunologic, Humans, Neoplasms, T-Lymphocytes, Cytotoxic, CD4-Positive T-Lymphocytes, Immunotherapy, Adoptive
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