Language
English
Publication Date
5-8-2025
Journal
JCI Insight
DOI
10.1172/jci.insight.187531
PMID
40198126
PMCID
PMC12128997
PubMedCentral® Posted Date
4-8-2025
PubMedCentral® Full Text Version
Post-print
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 antitumor cytolysis by transferring FAs into developing metastatic tumors. We describe a process of transendothelial FA delivery via endosomes that requires mTORC1 activity. Thus, endothelial cell-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.
Keywords
Fatty Acids, Animals, Tumor Microenvironment, Mice, Mechanistic Target of Rapamycin Complex 1, Humans, Neoplasm Metastasis, Endothelial Cells, Regulatory-Associated Protein of mTOR, Cell Line, Tumor, Everolimus, Female
Published Open-Access
yes
Recommended Citation
Edwards, Deanna N; Wang, Shan; Kane, Kelby; et al., "Increased Fatty Acid Delivery by Tumor Endothelium Promotes Metastatic Outgrowth" (2025). Faculty, Staff and Students Publications. 8028.
https://digitalcommons.library.tmc.edu/baylor_docs/8028