Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.187531.
Abstract
Metastatic outgrowth in distant microscopic niches requires sufficient nutrients, including fatty acids (FAs), to support tumor growth and to generate an immunosuppressive tumor microenvironment (TME). However, despite the important role of FAs in metastasis, the regulation of FA supply in metastatic niches has not been defined. In this report, we show that tumor endothelium actively promotes outgrowth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. We describe a process of transendothelial FA delivery via endosomes that requires mTORC1 activity. Thus, endothelial-specific targeted deletion of Raptor (RptorECKO), a unique component of the mTORC1 complex, significantly reduced metastatic tumor burden that was associated with improved markers of T cell cytotoxicity. Low dose everolimus that selectively inhibited endothelial mTORC1 improves immune checkpoint responses in metastatic disease models. This work reveals the importance of transendothelial nutrient delivery to the TME, highlighting a future target for therapeutic development.
Authors
Deanna N Edwards, Shan Wang, Kelby Kane, Wenqiang Song, Laura C. Kim, Verra M. Ngwa, Yoonha Hwang, Kevin C. Ess, Mark R. Boothby, Jin Chen
