Oral nano-delivery of a gut microbial metabolite enhances T cell stemness for cancer immunotherapy

Kai Han, Young Seok Cho, Mariko Takahashi, Xingwu Zhou, Hannah E. Dobson, Kim Hutchings, Yuesong Wu, Youngseo Na, Fang Xie, Julia Crowther, Jinmei Wu, Jin Xu, Chuan Lee, Himani Jasewicz, Yujin Kim, Minal Nenwani, Olamide Animasahun, Fulei Wuchu, Anthony Andren, Harrison Wong, Emma Camp, Ziye Wan, Qi Wu, Li Zhang, Cheng Xu, Katherine Dong, Yao Xu, Anna Schwendeman, Grace Y. Chen, Yuying Xie, Costas A. Lyssiotis, Martin Clasby, Deepak Nagrath, Yu Leo Lei & James J. Moon

Nature Nanotechnology | 21 | 1338–1349 (2026)

Gut microbial metabolites play crucial roles in regulating systemic immunity, but their mechanisms and limited drug-like properties remain unresolved. Here we report an oral nano-formulation that leverages gut microbial metabolites to modulate T cell metabolism and amplify antitumour immunity. Through an in vitro screening of gut microbial metabolites, we identified 3,4-dihydroxybenzoic acid that improved adoptive T cell therapy and enhanced CD8+ T cell stemness by suppressing glycolysis and regulating the Akt-mTORC1-Myc pathway. To harness the potency of 3,4-dihydroxybenzoic acid for systemic cancer immunotherapy, we engineered a 3,4-dihydroxybenzoic acid prodrug nano-emulsion, significantly increasing its oral absorption and half-life. In multiple murine tumour models, the oral nano-emulsion enhanced the expansion of antigen-specific, stem-like CD8+ T cells, sensitizing tumours to anti-PD-1 blockade and exerting robust antitumour efficacy. By integrating nanotechnology with microbial-metabolite-based immunotherapy, this study establishes a mechanistic link between the gut microbiota and T cell immunity, offering a promising approach for cancer immunotherapy.