Nanodrug Modulates Premetastatic Niche and Suppresses Metastatic Lung Adenocarcinoma via Programmed Cell Death Ligand 1 Blockade and STING Pathway Activation.

Abstract

Metastasis is a major cause of mortality in patients with lung adenocarcinoma (LUAD), with the premetastatic niche (PMN) playing a crucial role in LUAD metastasis. However, the mechanisms underlying PMN formation in LUAD remain poorly understood, hindering therapeutic advancements. Herein, we developed a PMN-targeted nanodrug by coating programmed cell death protein 1 (PD-1)-high expressed T cell membranes on the surface of STING activator 2'3'-cGAMP-loaded PLGA@MnO₂ nanoparticles (PSMP) for suppressing metastatic LUAD. Additionally, the immune profiles of PMN in LUAD were investigated using single-cell RNA-sequencing, which showed that the recruitment of programmed cell death ligand 1 (PD-L1)-high expressed myeloid-derived suppressor cells (MDSCs) drives the PMN formation in LUAD, leading to an immunosuppressive microenvironment. The in vivo results showed that the nanodrug exhibited excellent PMN-targeting capability and efficiently destroyed PMN by blocking the high expression of PD-L1 on MDSCs and activating the STING signaling pathway, thereby suppressing metastasis occurrence. Collectively, this study provides a generalizable concept that the combination of exploring characteristics of immunosuppressive PMN in LUAD and developing effective nanotherapeutics is an effective option for combating metastatic LUAD.