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Gasdermin D–mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma

Long-term senescent cells exhibit a secretome termed the senescence-associated secretory phenotype (SASP). Although the mechanisms of SASP factor induction have been intensively studied, the release mechanism and how SASP factors influence tumorigenesis in the biological context remain unclear. In this study, using a mouse model of obesity-induced hepatocellular carcinoma (HCC), we identified the release mechanism of SASP factors, which include interleukin-1β (IL-1β)– and IL-1β–dependent IL-33, from senescent hepatic stellate cells (HSCs) via gasdermin D (GSDMD) amino-terminal–mediated pore. We found that IL-33 was highly induced in senescent HSCs in an IL-1β–dependent manner in the tumor microenvironment. The release of both IL-33 and IL-1β was triggered by lipoteichoic acid (LTA), a cell wall component of gut microbiota that was transferred and accumulated in the liver tissue of high-fat diet–fed mice, and the release of these factors was mediated through cell membrane pores formed by the GSDMD amino terminus, which was cleaved by LTA-induced caspase-11. We demonstrated that IL-33 release from HSCs promoted HCC development via the activation of ST2-positive Treg cells in the liver tumor microenvironment. The accumulation of GSDMD amino terminus was also detected in HSCs from human NASH-associated HCC patients, suggesting that similar mechanism could be involved in a certain type of human HCC. These results uncover a release mechanism for SASP factors from sensitized senescent HSCs in the tumor microenvironment, thereby facilitating obesity-associated HCC progression. Furthermore, our findings highlight the therapeutic potential of inhibitors of GSDMD-mediated pore formation for HCC treatment. Description SASP factors are released via the gasdermin D N-terminal cell membrane pore from senescent hepatic stellate cells. Release of IL-33 in HCC Secretion of senescence-associated secretory phenotype (SASP) factors by senescent hepatic stellate cells promotes the development of hepatocellular carcinoma (HCC); however, the release mechanism is not well understood. Yamagishi et al. used an obesity-induced HCC mouse model to study SASP factor release from hepatic stellate cells within tumors. IL-33 release was triggered by lipoteichoic acid, which accumulated in the livers of obese mice. Full-length IL-33 was cleaved to its short active form and released into the tumor microenvironment through gasdermin D N-terminal pores. Secreted IL-33 bound to ST2+ Treg cells, resulting in impaired CD8+-mediated antitumor immunity and the development of HCC. These findings shed light on SASP factor release and suggest that targeting IL-33 release from senescent cells may be an attractive therapy for HCC.