Senescent Tumoral HLA-E Reshapes Microenvironment through Impairing NK Cell-Dendritic Cell-T Cell Network in Malignant Pleural Effusion from Lung Cancer

<b>Background:</b> Malignant pleural effusion (MPE) is ominous in lung cancer patients. However, comprehensive studies of both innate and adaptive immune responses within the pleural tumor microenvironment remain limited. <b>Methods:</b> We collected samples from patients with heart failure and lung cancer-MPE. By single-cell RNA sequencing, we analyzed alternations in cancer cells, NK cells, DCs, and T cells. Key cytokines involving in cell-cell interactions were quantified using Luminex or ELISA, while HLA-E and aging markers were assessed via immunohistochemistry. <b>Results:</b> Our findings revealed that CD56⁺CD16⁺ and CD56⁻CD16⁻ NK cells exhibited reduced cytotoxicity, mainly through HLA-E-expressing senescent cancer cells interacting with NK cells inhibitory receptor, leading to NK cell dysfunction and reduced XCL2 expression, which might impair cDC1 recruitment. Consequently, aDC2 cells evolved into exhausted phenotype, resulting in inadequate T cell activation. In CD8 T cells, transcription factors such as <i>FOXO1</i> contributed to diminished cytotoxicity. Despite presence of GZMA CD4 T cells, their cytotoxicity was suppressed in MPE. Th1-like and Th2-like regulatory T cells further inhibited CD4 T cell responses. Key molecules, CXCL16, BAG6, and IL-7, bridging innate and adaptive immunity conferred poor prognosis. <b>Conclusions:</b> Our study demonstrates that senescent cancer cells promote immunoevasion through HLA-E, suppressing NK cell cytotoxicity, impairing DC function, and disrupting T cell activation. Cell-cell interaction and imbalanced Th1/Th2 contribute to microenvironmental remodeling, driving disease progression. These findings provide insights into the immunological landscape and therapeutic targets for intervention.