Gut microbiota-derived hexa-acylated lipopolysaccharides enhance cancer immunotherapy responses Journal Article
| Authors: | Sardar, P.; Beresford-Jones, B. S.; Xia, W.; Shabana, O.; Suyama, S.; Ramos, R. J. F.; Soderholm, A. T.; Tourlomousis, P.; Kuo, P.; Evans, A. C.; Imianowski, C. J.; Conti, A. G.; Wesolowski, A. J.; Baker, N. M.; McCord, E. A. L.; Okkenhaug, K.; Whiteside, S. K.; Roychoudhuri, R.; Bryant, C. E.; Cross, J. R.; Pedicord, V. A. |
| Article Title: | Gut microbiota-derived hexa-acylated lipopolysaccharides enhance cancer immunotherapy responses |
| Abstract: | The gut microbiome modulates immunotherapy treatment responses, and this may explain why immune checkpoint inhibitors, such as anti-PD-1, are only effective in some patients. Previous studies correlated lipopolysaccharide (LPS)-producing gut microbes with poorer prognosis; however, LPS from diverse bacterial species can range from immunostimulatory to inhibitory. Here, by functionally analysing faecal metagenomes from 112 patients with melanoma, we found that a subset of LPS-producing bacteria encoding immunostimulatory hexa-acylated LPS was enriched in microbiomes of clinical responders. In an implanted tumour mouse model of anti-PD-1 treatment, microbiota-derived hexa-acylated LPS was required for effective anti-tumour immune responses, and LPS-binding antibiotics and a small-molecule TLR4 antagonist abolished anti-PD-1 efficacy. Conversely, oral administration of hexa-acylated LPS to mice significantly augmented anti-PD-1-mediated anti-tumour immunity. Penta-acylated LPS did not improve anti-PD-1 efficacy in vivo and inhibited hexa-acylated LPS-induced immune activation in vitro. Microbiome hexa-acylated LPS therefore represents an accessible predictor and potential enhancer of immunotherapy responses. © The Author(s) 2025. |
| Keywords: | controlled study; treatment response; antibiotic agent; unclassified drug; human cell; major clinical study; genetics; nonhuman; flow cytometry; mass spectrometry; quality control; mouse; animal; metabolism; animals; mice; animal tissue; cancer immunotherapy; melanoma; classification; animal experiment; animal model; antineoplastic activity; prediction; mice, inbred c57bl; c57bl mouse; toll like receptor 4; immunology; immune response; immunotherapy; escherichia coli; tumor immunity; lipopolysaccharide; monocyte; drug therapy; intestine flora; microbiology; macrophage; cytokine release; feces; antibody; therapy; bacterium; feces analysis; programmed death 1 receptor; toll-like receptor 4; open reading frame; bacteria; metagenome; lipopolysaccharides; klebsiella pneumoniae; procedures; immune checkpoint inhibitor; mesentery lymph node; humans; human; female; article; programmed cell death 1 receptor; broadly neutralizing antibody; immune checkpoint inhibitors; shotgun sequencing; gastrointestinal microbiome; thp-1 cell line; anti pd 1 antibody; hexa acylated lipopolysaccharide; resatorvid; toll like receptor 4 antagonist; toll like receptor antagonist; porphyromonas gingivalis |
| Journal Title: | Nature Microbiology |
| Volume: | 10 |
| Issue: | 3 |
| ISSN: | 2058-5276 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-03-01 |
| Start Page: | 795 |
| End Page: | 807 |
| Language: | English |
| DOI: | 10.1038/s41564-025-01930-y |
| PUBMED: | 39929976 |
| PROVIDER: | scopus |
| PMCID: | PMC11879847 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
