Plant-nanoparticles enhance anti-PD-L1 efficacy by shaping human commensal microbiota metabolites
Diet has emerged as a key impact factor for gut microbiota function. However, the complexity of dietary components makes it difficult to predict specific outcomes. Here we investigate the impact of plant-derived nanoparticles (PNP) on gut microbiota and metabolites in context of cancer immunotherapy with the humanized gnotobiotic mouse model. Specifically, we show that ginger-derived exosome-like nanoparticle (GELN) preferentially taken up by Lachnospiraceae and Lactobacillaceae mediated by digalactosyldiacylglycerol (DGDG) and glycine, respectively. We further demonstrate that GELN aly-miR159a-3p enhances anti-PD-L1 therapy in melanoma by inhibiting the expression of recipient bacterial phospholipase C (PLC) and increases the accumulation of docosahexaenoic acid (DHA). An increased level of circulating DHA inhibits PD-L1 expression in tumor cells by binding the PD-L1 promoter and subsequently prevents c-myc-initiated transcription of PD-L1. Colonization of germ-free male mice with gut bacteria from anti-PD-L1 non-responding patients supplemented with DHA enhances the efficacy of anti-PD-L1 therapy compared to controls. Our findings reveal a previously unknown mechanistic impact of PNP on human tumor immunotherapy by modulating gut bacterial metabolic pathways.
Authors
- Craig J. McClain (ORCID: https://orcid.org/0000-0002-7219-8939)
- Mukesh K. Sriwastva (ORCID: https://orcid.org/0000-0003-4370-4625)
- Jae Yeon Hwang (ORCID: https://orcid.org/0000-0002-7247-0146)
- Qingbo Xu (ORCID: https://orcid.org/0000-0003-2474-8155)
- Xin Hu (ORCID: https://orcid.org/0000-0001-8834-0090)
- Zhanxu Liu
- Juw Won Park (ORCID: https://orcid.org/0000-0002-4610-6893)
- Maiying Kong (ORCID: https://orcid.org/0000-0002-7313-9084)
- Raobo Xu (ORCID: https://orcid.org/0000-0002-7178-8961)
- Huang‐Ge Zhang (ORCID: https://orcid.org/0000-0001-9665-9202)
- Minmin Liu (ORCID: https://orcid.org/0000-0001-9391-7739)
- Michael L. Merchant (ORCID: https://orcid.org/0000-0003-4128-4057)
- Lifeng Zhang (ORCID: https://orcid.org/0000-0003-2236-9936)
- Xiang Zhang (ORCID: https://orcid.org/0000-0003-1102-6313)
- Yun Teng (ORCID: https://orcid.org/0000-0001-6428-2551)
- Chao Luo (ORCID: https://orcid.org/0000-0002-6233-3287)
- Fangyi Xu (ORCID: https://orcid.org/0000-0002-6764-8616)
- Jingyao Mu
- Xiaolan Qiu (ORCID: https://orcid.org/0000-0002-8517-3415)
- Junjie Yan (ORCID: https://orcid.org/0000-0001-6923-7936)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- University of Louisville (US)
- Xuzhou Medical College (CN)
- Huaian First People’s Hospital (CN)
- Louisville VA Medical Center (US)
- Second People’s Hospital of Huai’an (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-03
- DOI
- https://doi.org/10.1038/s41467-025-56498-2
- Citations
- 53
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 42.72
Funders
- Biomedical Laboratory Research and Development, VA Office of Research and Development
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism
- National Institute of General Medical Sciences
- National Institute of Environmental Health Sciences
- National Center for Complementary and Integrative Health