Dihydroartemisinin suppresses YAP1/SP1-associated SLC6A6 expression to remodel taurine homeostasis and increase intratumoral CD8+T cells in hepatocellular carcinoma.

Abstract

Taurine availability is critical for CD8+T-cell survival and effector function. Dihydroartemisinin (DHA), a bioactive artemisinin derivative, exhibits antitumor activity in hepatocellular carcinoma (HCC); however, whether DHA enhances CD8+T-cell antitumor immunity by remodeling taurine homeostasis remains unknown. In the present study, we found that the expression of solute carrier family 6 member 6 (SLC6A6) and specificity protein 1 (SP1) was elevated in publicly available human HCC datasets, whereas reduced taurine levels were observed in liver tumor tissues from mice with DEN/TCPOBOP-induced HCC. Genetic inhibition of Yes-associated protein 1 (YAP1) reduced SP1 and SLC6A6 expression and increased extracellular and tumor-associated taurine levels in cellular and mouse models of HCC. Furthermore, DHA treatment reduced YAP1, SP1, and SLC6A6 expression and the detectable association between YAP1 and SP1, accompanied by increased extracellular taurine levels. These metabolic changes were accompanied by increased intratumoral CD8-associated and granzyme B (GZMB)-associated immune signals and reduced tumor growth. Notably, the effects of DHA on taurine homeostasis, immune-associated phenotypes, and tumor progression were markedly attenuated in YAP1-deficient models, indicating that tumor-cell YAP1 contributes to the molecular and metabolic responses to DHA. Collectively, our findings identify a YAP1-SP1-SLC6A6 regulatory module involved in taurine metabolic remodeling in HCC. DHA suppresses YAP1/SP1-associated SLC6A6 expression and remodels taurine homeostasis with increased intratumoral CD8+T cells and reduced tumor growth. These findings suggest a potential link between DHA-induced metabolic changes and immune-associated phenotypes in HCC.