Nicotinamide riboside enhances adoptive T cell therapy by promoting memory differentiation and metabolic fitness

  • Mol Ther. 2026 Jun 2:S1525-0016(26)00470-3. doi: 10.1016/j.ymthe.2026.05.026.
Nengzhi Pang  1 ,  Jinping He  2 ,  Lei Pei  3 ,  Ying Xiao  3 ,  Yingying Gu  3 ,  Cheng Zhi  4 ,  Xuye Lai  3 ,  Mingtao Chen  3 ,  Qiyao Xiao  3 ,  Xueqian Wu  3 ,  Zhenfeng Zhang  5 ,  Lili Yang  6
Affiliations
  • 1. Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong 510275, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education, International Collaborative Research Center for the Development and Utilization of Tropical Food for Special Medical Purpose, School of Public Health, Hainan Medical University, Haikou, Hainan 571199, China; Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan 571199, China.
  • 2. Radiology Center, Guangzhou Key Laboratory for Research and Development of Nano-Biomedical Technology for Diagnosis and Therapy, Guangdong Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumour Microenvironment, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China; Department of Ultrasound, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510000, China.
  • 3. Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
  • 4. Department of Pathology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, China.
  • 5. Radiology Center, Guangzhou Key Laboratory for Research and Development of Nano-Biomedical Technology for Diagnosis and Therapy, Guangdong Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumour Microenvironment, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China. Electronic address: [email protected].
  • 6. Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong 510275, China. Electronic address: [email protected].
PMID: 42231576 DOI: 10.1016/j.ymthe.2026.05.026
Abstract

Enhancing the efficacy of adoptively transferred T cells is essential for successful immunotherapy. The cytotoxic activity of these T cells is closely related to their mitochondrial function, which plays a critical role in T cell differentiation. This study explored the potential of nicotinamide riboside (NR), known to enhance mitochondrial function, to improve the efficacy of adoptively transferred CD8+ T cells against hepatocellular carcinoma (HCC). In subcutaneous and metastatic HCC tumor models, NR treatment significantly improved the effectiveness of adoptive T cell therapy (ACT). NR promoted the differentiation of CD44hiCD62Lhi central memory T cells (TCM) and upregulated memory-associated genes (Tcf7, CCR7, and FOXO1). Upon restimulation, NR-treated CD8+ T cells exhibited strong recall responses, as evidenced by metabolic reprogramming and increased cytokine production. Furthermore, RNA Sequencing revealed an increased expression of FOXO1 and its target genes. Inhibition of FOXO1 partially reversed the beneficial effects of NR on mitochondrial fitness and cytotoxic function, suggesting a role for Foxo1-associated pathways in mediating these effects. In summary, NR improved mitochondrial fitness and promoted TCM differentiation, in part through a transcriptional program associated with FOXO1, thereby improving the efficacy of ACT. These findings identify NR as a promising and translatable metabolic Adjuvant for HCC immunotherapy.

Keywords
CD8(+) T cell; HCC; adoptive T cell therapy; anti-tumor capacity; central memory T cell; hepatocellular carcinoma; nicotinamide riboside.
Products