Translational Nanotherapeutics Reprograms Immune Microenvironment in Malignant Pleural Effusion of Lung Adenocarcinoma

Malignant pleural effusion (MPE) remains a treatment bottleneck in advanced lung cancer, due to its complicated microenvironments and "cold" immunity. Therefore, the search for therapeutic drugs to transform MPE to functionally "hot" one could advance the development of effective immunotherapeutic strategy. Herein, translational selenium nanoparticles coated with immune-modulating macromolecule lentinan (SeNPs@LNT) are designed to restore the dysfunctional immune cells in patient-derived MPE microenvironment. Internalization of the SeNPs@LNT can effectively reduce the immunosuppressive status by enhancing the proliferation of CD4⁺ T cells and natural killer cells, and remodeling the tumor associated macrophages into tumoricidal M1 phenotype in MPE derived from patients presenting low Se levels in blood and pleural effusion. Th1, cytotoxic T cell, γδ T, and B cell functions are upregulated, and Th2, Th17, and Treg cells activity is downregulated. Furthermore, SeNPs@LNT can be gradually metabolized into SeCys2 to promote the production of metabolites associated with tumor growth inhibition and immune response activation in MPE microenvironment. In contrast, lung cancer markers and vitamin B6 metabolism are decreased. The translational SeNP-based nanotherapeutic strategy restores functional "cold" MPE to "hot" MPE to activate the immune responses of various immune cells in MPE of lung cancer patients.