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 has now discovered that all-trans retinoic acid (ATRA), a vitamin A derivative, may help prevent such exhaustion and enhance the efficacy of immune checkpoint inhibitors.

KAIST (President Choongsik Bae) announced on September 8 that a 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), a form of active vitamin A metabolite, suppresses the "terminal exhaustion" of CD8⁺ T cells that attack cancer cells within brain tumors, and can enhance the effect of anti-PD-1 immunotherapy. Anti-PD-1 is a leading immuno-oncology drug (immune checkpoint inhibitor).

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 sufficient therapeutic effect is difficult even with anti-PD-1 therapy, which releases the "brake" cancer cells impose on immune cells.

To address this problem, the research team tried to figure out how to prevent immune cells from reaching total burnout, rather than how to revive the cells. Subsequently, the research team 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.

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 dead. By combining the two approaches, the researchers propose a new combination-therapy strategy that could help overcome the limitations of existing immunotherapy.

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 non-responders. Separately, in an immunotherapy-naïve glioblastoma cohort, patients with a higher proportion of retinoic-acid-responsive CD8⁺ T cells showed significantly better overall survival. The team noted 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, dosages, and combination effects with immunotherapy drugs before it can be applied to actual brain tumor treatment.

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 anti-cancer function. He also noted 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.

The study was conducted with Dr. In Kang, a postdoctoral researcher in KAIST's Department of Biological Sciences, as first author, and Professor Heung Kyu Lee as corresponding author. Professor Jae-Byum Chang from KAIST's Department of Materials Science and Engineering, Professor Sung Ki Lee from Konyang University College of Medicine, and Professor Stephen Ahn from Seoul St. Mary's Hospital also participated in the research. The findings were published on August 26 in the international journal Signal Transduction and Targeted Therapy.

※ Paper title: All-trans retinoic acid suppresses CD8⁺ T-cell terminal exhaustion and potentiates anti-PD-1 therapy in glioblastoma
DOI: 10.1038/s41392-026-02852-9

This work was supported by National Research Foundation of Korea grants (RS-2023-NR077244, RS-2024-00439735, RS-2026-25509011 to H.K.L. and RS-2024-00352668 to S.A.). This study was also supported by the Samsung Science and Technology Foundation (SSTF-BA1902-05 to H.K.L.), Republic of Korea. This research was also supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2023-00302794 to J.B.C.).