Extracellular vesicle-LncRNA HOTAIR modulates esophageal cancer chemoresistance and immune microenvironment via miR-375/CDH2 pathway.

Chemoresistance and immune evasion remain significant barriers to effective esophageal cancer (EC) treatment. This study explores the mechanistic role of extracellular vesicles (EVs) delivering LncRNA HOTAIR in modulating these processes. Using transcriptomic profiling, LncRNA HOTAIR was identified as a critical factor in EC progression. Its interaction with miR-375 was examined via luciferase reporter assays and RNA immunoprecipitation. Paclitaxel-resistant EC cells were treated with EVs containing HOTAIR, and the functional impact on proliferation, migration, invasion, and immune response was assessed through in vitro and in vivo models. LncRNA HOTAIR in EVs enhanced paclitaxel resistance by suppressing miR-375 and increasing CDH2 expression. Furthermore, HOTAIR promoted immune escape by upregulating PD-L1, impairing T-cell-mediated cytotoxicity. These changes were validated in patient-derived EC models. This study demonstrates that EV-LncRNA HOTAIR mediates chemoresistance and immune evasion in EC by targeting the miR-375/CDH2 axis. These findings provide a foundation for novel therapeutic interventions targeting EV-HOTAIR.