Probiotics functionalized with a gallium-polyphenol network modulate the intratumor microbiota and promote anti-tumor immune responses in pancreatic cancer

Zi-Yi Han, Zhuang-Jiong Fu, Yu-Zhang Wang, Cheng Zhang, Qi-Wen Chen, Jia-Xin An and Xian-Zheng Zhang ()
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Zi-Yi Han: Wuhan University
Zhuang-Jiong Fu: Wuhan University
Yu-Zhang Wang: Wuhan University
Cheng Zhang: Wuhan University
Qi-Wen Chen: Wuhan University
Jia-Xin An: Wuhan University
Xian-Zheng Zhang: Wuhan University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract The intratumor microbiome imbalance in pancreatic cancer promotes a tolerogenic immune response and triggers immunotherapy resistance. Here we show that Lactobacillus rhamnosus GG probiotics, outfitted with a gallium-polyphenol network (LGG@Ga-poly), bolster immunotherapy in pancreatic cancer by modulating microbiota-immune interactions. Upon oral administration, LGG@Ga-poly targets pancreatic tumors specifically, and selectively eradicates tumor-promoting Proteobacteria and microbiota-derived lipopolysaccharides through a gallium-facilitated disruption of bacterial iron respiration. This elimination of intratumor microbiota impedes the activation of tumoral Toll-like receptors, thus reducing immunosuppressive PD-L1 and interleukin-1β expression by tumor cells, diminishing immunotolerant myeloid populations, and improving the infiltration of cytotoxic T lymphocytes in tumors. Moreover, LGG@Ga-poly hampers pancreatic tumor growth in both preventive and therapeutic contexts, and amplifies the antitumor efficacy of immune checkpoint blockade in preclinical cancer models in female mice. Overall, we offer evidence that thoughtfully designed biomaterials targeting intratumor microbiota can efficaciously augment immunotherapy for the challenging pancreatic cancer.

Date: 2024
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DOI: 10.1038/s41467-024-51534-z

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