CD93-targeted resveratrol-loaded PLGA nanoparticles remodel CD8⁺ T cell metabolism through AIF-mediated oxidative phosphorylation to overcome lung cancer immunotherapy resistance

Lung cancer (LC) remains a leading cause of cancer-related mortality worldwide, and the limited efficacy of immunotherapy due to treatment resistance underscores the urgent need for new therapeutic strategies. In the present study, CD93-targeted poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating resveratrol (CD93-NPs@RSV) were developed to remodel the metabolic fitness of CD8⁺ tumor-infiltrating lymphocytes. The nanoparticles were precisely engineered and characterized using dynamic light scattering, transmission electron microscopy, and in vivo imaging, which confirmed their stability and tumor-targeting capability. Mechanistic studies revealed that CD93-NPs@RSV suppressed CD93 expression, facilitated apoptosis-inducing factor (AIF) mitochondrial translocation, and activated oxidative phosphorylation (OXPHOS), thereby enhancing T cell function in the tumor microenvironment. Transcriptomic and proteomic analyses further confirmed regulation of the CD93-AKT-PAK5-AIF signaling axis. In a Lewis LC model, CD93-NPs@RSV significantly inhibited tumor progression and displayed strong synergy with anti-PD-1 therapy, resulting in improved survival outcomes. Collectively, our study demonstrates that CD93-NPs@RSV provide a powerful nanotechnology-driven approach to reverse immunotherapy resistance by reprogramming T cell metabolism. These findings establish a promising paradigm for precision cancer immunotherapy and underscore the translational potential of targeted nanomedicine in overcoming therapeutic bottlenecks in LC.