Microbiome-derived hydroxyphenyl propanoates enhance antitumour immunity by potentiating gasdermin D activity in tumour-associated myeloid cells

The microbiome plays a critical role in 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 a class of microbiome-derived metabolites called hydroxyphenyl propanoates (HPP) that enhance tumour immune surveillance and response to immune checkpoint blockade (ICB) therapy in mice. HPPs function as potentiators of innate immune signalling in tumour-associated myeloid cells by promoting cleavage of the pore-forming protein gasdermin D (GSDMD), a critical effector of inflammasome function. This enhances the secretion of proinflammatory cytokines, such as IL-1 family members, while simultaneously protecting against pyroptosis. Secreted IL-1 family cytokines in turn elicit autocrine and paracrine inflammatory signaling in tumour-infiltrating leukocytes. HPP supplementation increases anticancer T cell function, improves disease control and extends overall survival (OS) in tumour-bearing mice harboring complex microbiomes or those treated with broad-spectrum antibiotics. In humans, GSDMD activation is associated with a favourable response to PD-1 blockade therapy in patients with advanced stage melanoma. Our study uncovers a molecular mechanism of regulation over host antitumour immunity that is modifiable and can be harnessed for improved cancer immunotherapy in a broad spectrum of patients.