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.