Microbiome-derived hydroxyphenyl propanoate promotes antitumour immunity by enhancing Gasdermin D cleavage in tumour-associated myeloid cells

The microbiome has a significant impact on immune health and response to immune-stimulating treatments, including cancer immunotherapy. However, the molecular mechanisms by which commensal microbes influence cancer immunology remain poorly understood. Here, we report on the discovery of a class of microbiome-derived metabolites called hydroxyphenyl propanoates (HPP) that enhance tumour immune surveillance in mice and synergize with immune checkpoint blockade (ICB) therapy. HPP molecules act as broad spectrum potentiators of innate immune signalling pathways in tumour-associated myeloid cells by promoting cleavage of the pore-forming protein gasdermin D (GSDMD), a critical effector of canonical and non-canonical inflammasome signalling. Heightened secretion of proinflammatory cytokines from HPP-treated myeloid cells, including IL-1β, promotes NF-κB activity within tumour-infiltrating leukocytes. This leads to heightened anticancer CD8 T cell accumulation, tumour regression, and long-term cancer control by immune checkpoint therapy in mice. Human peripheral blood mononuclear cells (PBMCs) respond to HPP treatment in a similar way. GSDMD cleavage also associates with a favourable response to ICB therapy in advanced stage melanoma patients. Taken together, our study uncovers a mechanism of microbiome-mediated modulation of host antitumour immunity that is modifiable and can be harnessed to enhance the efficacy of cancer immunotherapy. The proteomics part involved searching for hydroxuphenyl pyruvate interactors by using thermal profiling. TMT 10 plex and a method utilizing real-time search was used for quantification.