For decades, cancer immunotherapy has focused primarily on CD8+ cytotoxic T lymphocytes as the main executors of tumor cell killing. However, growing clinical and single-cell sequencing evidence shows that CD4+ T cells are far more than immune “helpers.” Within tumors, CD4+ T cell subsets exhibit remarkable heterogeneity, ranging from cytotoxic CD4+ CTLs to immunosuppressive regulatory T cells (Tregs). At the same time, chronic antigen exposure in the tumor microenvironment drives functional exhaustion, limiting therapeutic efficacy. The mechanisms underlying this duality—particularly how differentiation, metabolism, and inhibitory signaling interact—remain incompletely understood. Based on these challenges, there is an urgent need for in-depth investigation of CD4+ T cell biology in cancer.
In a review (DOI: 10.20892/j.issn.2095-3941.2025.0414) published in Cancer Biology & Medicine (January 2026), researchers from Zhejiang Cancer Hospital and collaborating institutions systematically examined the multifaceted roles of CD4+ T cells in tumor immunity. The study synthesizes advances in single-cell transcriptomics, metabolic profiling, and clinical immunotherapy to explain how CD4+ T cells simultaneously promote anti-tumor responses and contribute to immune evasion. The authors further analyze emerging therapeutic strategies targeting CD4+ T cell subsets, including immune checkpoint blockade, adoptive cell therapy, and neoantigen-based vaccines.
The review first outlines the biological foundations of CD4+ T cell activation. Upon recognizing tumor antigens presented by antigen-presenting cells, CD4+ T cells receive co-stimulatory and cytokine signals that determine their differentiation into functionally distinct subsets such as Th1, Th17, T follicular helper (Tfh), or regulatory T cells. Advances in single-cell RNA sequencing and spatial transcriptomics have revealed previously unrecognized CD4+ T cell subpopulations within tumors, including cytotoxic CD4+ CTLs capable of directly killing MHC-II–expressing tumor cells through granzyme and perforin release.
Beyond direct cytotoxicity, CD4+ T cells amplify anti-tumor immunity by producing IL-2 and IL-21 to sustain CD8+ T cell expansion, enhancing dendritic cell antigen presentation via CD40–CD40L signaling, and supporting B cell activation and tertiary lymphoid structure formation. However, the tumor microenvironment can reprogram CD4+ T cells into immunosuppressive Tregs or drive exhaustion characterized by upregulated inhibitory receptors such as PD-1, CTLA-4, and LAG-3. Metabolic stress—such as methionine depletion and mitochondrial dysfunction—further reinforces this dysfunctional state.
Importantly, immune checkpoint blockade can partially reverse CD4+ T cell exhaustion, restore effector function, and enhance therapeutic outcomes, highlighting their pivotal role in determining treatment responsiveness.
“CD4+ T cells are not merely assistants to CD8+ T cells—they are architects of the anti-tumor immune response,” the authors note. “Understanding their differentiation pathways, exhaustion programs, and metabolic vulnerabilities opens new opportunities to refine immunotherapy.” They emphasize that targeting CD4+ T cell subsets or restoring their functional fitness may improve response rates, overcome resistance to checkpoint inhibitors, and enable more durable tumor control across multiple cancer types.
The insights from this review carry significant clinical implications. CD4+ T cell status may serve as a predictive biomarker for immunotherapy response, particularly in PD-1/PD-L1 blockade. Therapeutic strategies that incorporate MHC-II epitopes into cancer vaccines could strengthen long-lasting CD4+ T cell memory. Combination checkpoint therapies, including LAG-3 inhibitors, may destabilize suppressive Tregs and enhance anti-tumor immunity. Furthermore, optimizing CD4+ CAR-T or adoptive T cell approaches could sustain cytotoxic responses in solid tumors. By integrating cellular, metabolic, and immunologic perspectives, this research reframes CD4+ T cells as central drivers of precision cancer immunotherapy rather than peripheral supporters.
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References
DOI
10.20892/j.issn.2095-3941.2025.0414
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0414
Funding information
This study was supported by The National Key Research and Development Program of China (Grant No. 2021YFA0910100) and Healthy Zhejiang One Million People Cohort (Grant No. K-20230085). C.H. was supported by National Natural Science Foundation of China (Grant Nos. 82304946 and 82573745), Post-doctoral Innovative Talent Support Program (Grant No. BX2023375), and 567 Foundation of Zhejiang Province (Grant No. LMS25H160006). Z.X. was supported by the National Natural Science Foundation of China (Grant No. 82473489), the Medical Science and Technology Project of Zhejiang Province (Grant No. WKJ-ZJ-2202), and the Natural Science Foundation of Zhejiang Province (Grant No. LBD24H290001). S.P. was supported by the National Natural Science Foundation of China (Grant No. 82403546).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).