Researchers at Johns Hopkins Medicine have discovered that exhausted T cells in head and neck squamous cell carcinoma share a distinct metabolic weak point centered on the enzyme glucose-6-phosphate dehydrogenase, or G6PD. Targeting this enzyme in laboratory experiments successfully reactivated these dormant immune cells, offering a potential path to improving immunotherapy efficacy beyond the current 17% to 23% response rate.
Blocking G6PD Helps Wake Exhausted T Cells
Understanding T-Cell Exhaustion: In many head and neck cancers, immune cells reach the tumor site but stop functioning because continuous activation burns them out, leaving them unable to destroy cancer cells.
The Metabolic Target: By analyzing single cells from patient biopsies, researchers found that these worn-out immune cells heavily rely on an enzyme called G6PD for energy, marking a specific vulnerability.
Potential Combination Therapy: Laboratory tests showed that blocking G6PD alongside immune checkpoint inhibitors successfully woke up the most exhausted T cells, though these findings require extensive human clinical trial confirmation.
Mapping Cellular Energy Inside Human Head and Neck Tumors
Head and neck squamous cell carcinoma—cancers originating in the cells lining the mouth, throat, and voicebox—accounts for approximately 890,000 new cases globally each year, making it the seventh most common cancer worldwide. While immune checkpoint inhibitors like anti-PD-1 antibodies have transformed oncology, they benefit only a small fraction of these patients. Researchers at the Johns Hopkins University School of Medicine, the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, and the Bloomberg~Kimmel Institute for Cancer Immunotherapy set out to investigate why these therapies fail so frequently.
To examine this issue, the team analyzed tumor tissue collected from patients enrolled in two phase II clinical trials where immunotherapy was administered prior to surgery. Participants received either the anti-PD-1 antibody nivolumab alone or combined with an antibody targeting interleukin-8, a signaling protein that directs immune cells toward inflammation. Tissue samples gathered both before treatment and four weeks later at the time of surgery allowed investigators to track cellular shifts.
Historically, investigating human tumor metabolism has faced a major technical barrier: standard laboratory assays require a large, pure population of a single cell type. Tumor biopsies, however, yield scarce mixtures of rare cell populations. As first author Sujeetha A. Rajakumar, Ph.D., explained, researchers previously relied heavily on mouse tissue and cells grown in dishes, which do not always reflect patient biology. The Johns Hopkins team bypassed this obstacle by simultaneously measuring individual cells’ metabolic machinery alongside their surface markers, capturing each cell’s identity, functional state, and metabolic profile all at once.
Identifying Vulnerabilities in Tumor-Infiltrating Immune Cells
Applying this single-cell profiling method to mucosal-associated invariant T (MAIT) cells, CD8+ T cells, and innate lymphoid cells (ILCs) yielded three key discoveries. First, the investigators identified a population of T cells within the tumors that remained metabolically fit and far less exhausted than neighboring cells. Second, the exhausted T cells displayed elevated levels of glucose-6-phosphate dehydrogenase (G6PD), pointing directly to a metabolic dependency. Third, a specific subset of ILCs exhibited a metabolic profile associated with immune suppression, which may create additional hurdles for checkpoint therapy.
To test whether these exhausted cells rely on the G6PD pathway, the researchers isolated tumor-infiltrating CD8+ T cells from untreated patients, sorting them by the presence of CD39, a protein linked to immunosuppression. They treated these cells with a G6PD inhibitor, an anti-PD-1 antibody, both agents together, or neither. The combination treatment induced the most substantial gene expression changes in the most exhausted cells and increased their secretion of CD27, a classic marker of T-cell activation.
| Experimental Parameter | Methodology & Scope | Key Observation |
|---|---|---|
| Clinical Trial Context | Phase II trials at Johns Hopkins Medicine evaluating pre-surgical immunotherapy (nivolumab alone or with anti-interleukin-8). | Allowed paired pre- and post-treatment tissue collection to map dynamic cellular changes. |
| Single-Cell Profiling | Simultaneous measurement of metabolic machinery and surface markers in human biopsy mixtures. | Uncovered a distinct metabolic weak point (elevated G6PD) in exhausted T cells. |
| Laboratory Testing | In vitro cultures of tumor-infiltrating CD8+ T cells sorted by CD39 expression. | Combining a G6PD inhibitor with an anti-PD-1 antibody successfully reactivated the most exhausted cells. |
Martin Alphonse, Ph.D., who serves as senior author and an assistant professor of dermatology at the Johns Hopkins University School of Medicine, highlighted the cooperative nature of the discoveries. Institutional infrastructure facilitated these translational insights, as noted by Charles W. Cummings, M.D.—professor of otolaryngology–head and neck surgery and professor of oncology—alongside co-author Carole Fakhry, M.D., M.P.H., who is the senior associate dean for clinical affairs at the Johns Hopkins University School of Medicine.
Consult a Specialist Before Seeking Experimental Trials
Patients currently undergoing or considering immunotherapy for head and neck squamous cell carcinoma must understand that targeting G6PD is strictly a laboratory discovery and not an approved clinical treatment. Always consult a qualified medical oncologist or head and neck cancer specialist before altering treatment regimens or seeking experimental clinical trials.
The Road Ahead for Immunometabolic Cancer Therapy
While the laboratory reactivation of exhausted T cells via G6PD inhibition provides a compelling new avenue for drug development, researchers stress that immediate clinical translation is not yet possible. Alphonse noted that these findings require confirmation in larger patient cohorts and must be evaluated in living biological systems rather than laboratory dishes alone before any therapeutic applications can be built.
References
- Immunometabolic profiling of T cells and innate lymphoid cells uncovers therapeutic targets to enhance immunotherapy in head and neck cancer. Rajakumar SA, Nanda N, Kim C, et al. Cancer Immunol Res. 2026. doi: 10.1158/2326-6066.CIR-26-0245
Disclaimer: This article is intended for informational and educational purposes only and does not constitute medical advice, diagnosis, or treatment. Patients should consult their healthcare providers for personalized medical guidance.
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