Tumor Microenvironment-Responsive Nano-Immunomodulators for Enhancing Chimeric Antigen Receptor-T Cell Therapy in Lung Cancer

Chimeric antigen receptor (CAR)-T cells have shown unparalleled efficacy in treating hematologic cancers, but their application in solid tumor treatment remains challenging due to the immunosuppressive tumor microenvironment (TME). It is highly significant to develop safe and efficient TME regulatory strategies for the adoptive cellular immunotherapy of tumors. Herein, a TME-responsive nanoimmunomodulator (FMANAC) is designed using a multicomponent coordination self-assembly method to reconstruct the immune chemokine gradient and overcome the suppression of CAR-T cell immunoactivity, thereby improving the infiltration and killing efficiency of CAR-T cells within tumors. The acidic TME induces the disassembly of FMANAC, followed by the drug release, in which C–C chemokine ligand 5 (CCL5) improves the disrupted chemotactic gradient within tumors, increasing CAR-T cell recruitment and infiltration into deep tissue; and NLG919 reverses indoleamine 2,3-dioxygenase (IDO)-mediated immunosuppression in TME to create a favorable environment for CAR-T cells to exert their killing function. In the H460 lung cancer animal model, this nanoregulatory strategy combined with engineered CD276 CAR-T cells, guided by multiplexed near-infrared-II fluorescence imaging for programmed administration, achieved significantly enhanced tumor treatment efficacy.