Vitamin A metabolite keeps immune cells active against recurrent brain tumors
· Medical Xpressby The Korea Advanced Institute of Science and Technology (KAIST)
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Immune cells can become exhausted after prolonged exposure to cancer, gradually losing their ability to attack tumor cells. This phenomenon is particularly pronounced in aggressive brain tumors and can severely limit the effectiveness of immunotherapy.
A KAIST research team led by Professor Heung Kyu Lee from the Department of Biological Sciences, in collaboration with researchers from Seoul St. Mary's Hospital and Konyang University College of Medicine, has found that all-trans retinoic acid (ATRA), an active vitamin A metabolite, suppresses the "terminal exhaustion" of CD8⁺ T cells that attack cancer cells within brain tumors and enhances the effect of anti-PD-1 immunotherapy. Anti-PD-1 is a leading immuno-oncology drug (immune checkpoint inhibitor).
The research is published in the journal Signal Transduction and Targeted Therapy.
When T cells burn out
Glioblastoma is a representative form of intractable brain cancer that frequently recurs even after surgery, radiation and chemotherapy. Immune checkpoint inhibitors have shown only limited effect against the disease. One key reason is that immune cells that infiltrate the tumor become exhausted after prolonged combat and lose their functional capacity.
Cells that reach a state of terminal exhaustion in particular lose their ability to kill cancer cells, much like soldiers who have exhausted themselves in prolonged combat. In this state, achieving a sufficient therapeutic effect is difficult even with anti-PD-1 therapy, which releases the "brake" cancer cells impose on immune cells.
ATRA helps preserve function
To address this problem, the research team tried to determine how to prevent immune cells from reaching total burnout rather than how to revive the cells. The research team then focused on the signaling of ATRA, an active vitamin A metabolite known to regulate cell differentiation and function.
Using an in vitro model that mimicked the hypoxic, exhaustion-promoting tumor microenvironment of brain tumors, the team induced exhaustion in CD8⁺ T cells. Those conditioned with ATRA progressed to terminal exhaustion at a markedly lower rate.
These cells also produced higher levels of immune molecules essential for attacking cancer—including interleukin-2 (IL-2), interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α)—and retained their ability to kill brain tumor cells.
The team also confirmed that ATRA activates WNT/β-catenin signaling within CD8⁺ T cells and increases TCF-1βBD, a TCF-1 isoform important for maintaining T-cell function. In simple terms, the vitamin A metabolite turns on a "function-preserving switch" inside immune cells, helping them avoid complete exhaustion even during prolonged combat with cancer cells.
Stronger results in combination
The effect was also confirmed in mouse glioma models. CD8⁺ T cells conditioned with ATRA maintained better immune function within the tumor, and oral administration of ATRA alone also increased both the number and function of tumor-infiltrating CD8⁺ T cells. As tumor burden decreased, survival was also extended.
Notably, in a model of recurrent brain tumors, anti-PD-1 immunotherapy alone showed only limited effect, but combining it with ATRA substantially improved tumor suppression and long-term survival outcomes.
In other words, if anti-PD-1 therapy releases the "brake" imposed on immune cells, ATRA keeps their "battery" from running completely down. By combining the two approaches, the researchers propose a new combination-therapy strategy that could help overcome the limitations of existing immunotherapy.
Patient data point the same way
The team also analyzed publicly available human glioblastoma datasets. In single-cell transcriptomic data from patients treated with anti-PD-1 therapy, CD8⁺ T cells from responders showed higher retinoic-acid-responsive and WNT signaling gene signatures than those from nonresponders.
Separately, in an immunotherapy-naive glioblastoma cohort, patients with a higher proportion of retinoic-acid-responsive CD8⁺ T cells showed significantly better overall survival.
The team notes that this study does not directly demonstrate ATRA's therapeutic efficacy in patients and that further clinical research will be needed to confirm appropriate administration methods, doses and combination effects with immunotherapy drugs before it can be applied to brain tumor treatment.
Clinical questions still remain
Professor Heung Kyu Lee said, "Glioblastoma is one of the cancers most resistant to immunotherapy because immune cells within the tumor readily become exhausted."
He added that the study is meaningful for presenting a molecular mechanism by which active vitamin A signaling helps prevent the terminal exhaustion of CD8⁺ T cells while preserving their anticancer function. He notes that future work validating more precise delivery methods or combination strategies could establish this as a new approach for improving the responsiveness of immunotherapy against intractable brain tumors.
More information
In Kang et al, All-trans retinoic acid suppresses CD8+ T-cell terminal exhaustion and potentiates anti-PD-1 therapy in glioblastoma, Signal Transduction and Targeted Therapy (2026). DOI: 10.1038/s41392-026-02852-9
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OncologyNeurologyAllergy and immunology Provided by The Korea Advanced Institute of Science and Technology (KAIST) Who's behind this story?
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