Migrasome-transported PTGES amplifies the PGE2 cascade in SPP1+ macrophages to drive oral leukoplakia carcinogenesis.

Oral leukoplakia (OLK) is a common oral potentially malignant disorder with a significant risk of transforming into oral squamous cell carcinoma (OSCC), yet the mechanisms remain poorly understood. Here we show that migrasomes, membranous organelles released by migrating cells, are detectable in epithelial cells of OLK and OSCC tissues and are more abundant in OSCC. Using carcinogenesis models, we transform human dysplastic oral keratinocyte (DOK) into oral carcinoma (DOK-TC) cells. Migrasomes derived from DOK-TC cells enhance interactions between DOK-TC cells and macrophages to promote carcinogenesis. Mechanistically, the uptake of prostaglandin E synthase (PTGES)-enriched migrasomes by macrophages increases PTGES expression and prostaglandin E2 secretion, which in turn induces an SPP1+ macrophage phenotype and promotes migration and proliferation. These findings uncover an unexplored migrasome-dependent immunomodulatory mechanism in OLK carcinogenesis and suggest migrasomal PTGES as a promising biomarker for early OSCC detection and a potential therapeutic target.