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Retinoic acid enhances γδ T cell cytotoxicity in nasopharyngeal carcinoma by reversing immune exhaustion

Published on Monday, 20 April 2026

Abstract

Recent studies have shown that the antitumor immunity of adaptive immune cells is regulated by Vitamin A (retinoic acid, RA). However, it remains unclear whether RA and retinoic acid receptor (RAR) signaling can modulate antitumor immunity by reversing immune exhaustion of innate-like γδ T cells in human nasopharyngeal carcinoma (NPC).

Periphery blood samples from patients with NPC were prospectively collected, and phenotypic and functional analyses of γδ T cells were performed using flow cytometry. Tumor-bearing models and RAR inhibitor approaches were utilized to investigate RA/RAR-mediated regulation of T cell immunoglobulin domain and mucin domain 3 (Tim-3) and the antitumor activity of γδ T cells.

Here, our findings indicate that immune exhaustion markers are highly expressed on peripheral αβ and γδ T cells in NPC patients. Serum RA levels are negatively correlated with the abundance of Tim-3 on circulating Vδ2 T cells. Mechanistic studies have demonstrated that RA/RAR signaling directly targets Vδ2 T cells, repressing Tim-3 expression, promoting NF-κB activation, and enhancing the production of antitumor-related cytokines.

Notably, RA supplementation improved the efficacy of Vδ2 T cell-mediated immunotherapy in human NPC by suppressing Tim-3 expression.

Collectively, these findings suggest that RA/RAR signaling plays a crucial role in reversing immune exhaustion and represents a promising target for γδ T cell antitumor immunotherapy.

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About this publication.

The Di Bella's Method: Use of Retinoids (40mg per day Beta-Carotene, 10mg per day ATRA and 10mg per day Axerophthol palmitate) with pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea (together with others chemical compounds) in Head and Neck Cancer:

- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

- The Di Bella Method (A Fixed Part - All-Trans Retinoic Acid, Analogues and/or Derivatives - Approximately 60mg per day orally: 40mg per day Beta-Carotene/β-Carotene, 10mg per day ATRA and 10mg per day Axerophthol palmitate);

- All-Trans-Retinoic Acid (ATRA - analogues and/or derivatives) - In vitro, review and in vivo publications;

- Solution of retinoids in vitamin E in the Di Bella Method biological multitherapy;

- The Di Bella Method (A Fixed Part - Alpha tocopheryl acetate/Vitamin E, approximately 20 grams per day orally);

- Cancer and Vitamin E (analogues and/or derivatives) and cancer - In vitro, review and in vivo publications;

- The Di Bella Method (A Fixed Part - Vitamin C/Ascorbic Acid, 2–4 grams, twice a day orally);

- The Di Bella Method (A Fixed Part - Dihydrotachysterol, Alfacalcidol, synthetic Vitamin D3);

- Vitamin D (analogues and/or derivatives) and cancer - In vitro, review and in vivo publications;

The Di Bella's Method: Use of Retinoic Acid, Beta-Carotene and Axerophthol palmitate with pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea - together with others chemical compounds - in several Oncological Pathologies:

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;

- Observations on the Report of a case of pulmonary adenocarcinoma with lymph node, hepatic and osseus metastasis;

- Pleural Mesothelioma: clinical records on 11 patients treated with Di Bella's Method;

- Malignant pleural mesothelioma, stage T3-T4. Consideration of a case study;

- Excellent result in a Mesothelioma case treated exclusively with Di Bella Method for over 4 years and still treatment with positive results;

- A case of advanced Multiple Myeloma treated with Di Bella Method (DBM) into total remission for 13 years;

- Neuroblastoma: Complete objective response to biological treatment;

- Cyclophosphamide plus Somatostatin, Bromocriptin, Retinoids, Melatonin and ACTH in the Treatment of Low-grade Non-Hodgkin’s Lymphomas at Advanced Stage: Results of a Phase II Trial;

- Relapse of High-Grade Non-Hodgkin’s Lymphoma After Autologous Stem Cell Transplantation: A Case Successfully Treated With Cyclophosphamide Plus Somatostatin, Bromocriptine, Melatonin, Retinoids, and ACTH;

- Low-grade Non-Hodgkin Lymphoma at Advanced Stage: A Case Successfully Treated With Cyclophosphamide Plus Somatostatin, Bromocriptine, Retinoids, and Melatonin;