Gut microbiota-derived hexa-acylated lipopolysaccharides enhance cancer immunotherapy responses
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.
Authors
- Rúben J. Ramos (ORCID: https://orcid.org/0000-0002-3350-0437)
- Justin R. Cross (ORCID: https://orcid.org/0000-0002-6356-057X)
- Charlotte J. Imianowski (ORCID: https://orcid.org/0000-0002-7116-7591)
- Rahul Roychoudhuri (ORCID: https://orcid.org/0000-0002-5392-1853)
- Paula Kuo (ORCID: https://orcid.org/0000-0002-2476-0018)
- Emily McCord
- Benjamin S. Beresford-Jones (ORCID: https://orcid.org/0000-0002-4699-8975)
- Panagiotis Tourlomousis (ORCID: https://orcid.org/0000-0002-6152-8066)
- Klaus Okkenhaug (ORCID: https://orcid.org/0000-0002-9432-4051)
- Clare Elizabeth Bryant (ORCID: https://orcid.org/0000-0002-2924-0038)
- Virginia A. Pedicord (ORCID: https://orcid.org/0000-0001-9625-3122)
- Satoshi Suyama (ORCID: https://orcid.org/0000-0002-1451-2125)
- Sarah K. Whiteside (ORCID: https://orcid.org/0000-0003-4354-4713)
- Puspendu Sardar (ORCID: https://orcid.org/0000-0001-8011-2915)
- Alexander C. Evans (ORCID: https://orcid.org/0000-0002-6363-2684)
- Amelia T. Soderholm (ORCID: https://orcid.org/0000-0001-7764-3651)
- Wangmingyu Xia (ORCID: https://orcid.org/0009-0006-5336-6884)
- Alexander J. Wesolowski (ORCID: https://orcid.org/0009-0006-1664-761X)
- Alberto G. Conti (ORCID: https://orcid.org/0000-0003-0725-337X)
- N. Baker
- Omar Shabana (ORCID: https://orcid.org/0000-0002-1947-8018)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of Cambridge (GB)
- Cambridge School (PT)
Publication Details
- Journal
- Nature Microbiology
- Published
- 2025-02-10
- DOI
- https://doi.org/10.1038/s41564-025-01930-y
- Citations
- 31
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 24.99
Funders
- Wellcome
- Rosetrees Trust
- Horizon 2020 Framework Programme
- Medical Research Council
- Biotechnology and Biological Sciences Research Council