Enhancing PD-1 blockade in NSCLC: Reprogramming tumor immune microenvironment with albumin-bound statins targeting lipid rafts and mitochondrial respiration

Non-small cell lung cancer (NSCLC) has shown limited response to immunotherapy, primarily due to an immunosuppressive tumor microenvironment characterized by hypoxia and lipid raft formation, which together inhibit T-cell infiltration and function, impeding effective immune responses. To address these challenges, we developed Abstatin, an albumin-bound fluvastatin formulation that targets lipid raft disruption and mitochondrial respiration inhibition, aiming to reduce hypoxia and destabilize lipid rafts to enhance T-cell activity within the tumor. Using bioinformatics analysis, in vitro assays, and in vivo studies in both murine and humanized PDX models, we demonstrated that Abstatin reprograms the NSCLC microenvironment by concurrently lowering hypoxia levels and lipid raft integrity, thereby restoring T-cell infiltration, enhancing cytotoxic T-cell function, and ultimately improving response to Anti-PD-1 therapy. Results showed that Abstatin significantly amplifies Anti-PD-1 efficacy with minimal toxicity, indicating a favorable safety profile for clinical use. This study highlights Abstatin as a promising immunotherapy adjuvant that addresses critical barriers in NSCLC by modulating metabolic pathways linked to immune resistance. Abstatin's approach, which combines modulation of cellular metabolism with immune sensitization, broadens the potential of immunotherapy and provides a practical, scalable strategy to enhance treatment outcomes in NSCLC and potentially other tumors, offering insights into combinatory cancer therapies. • Modulating lipid raft and mitochondrial metabolism for overcoming TME-induced immunotherapy resistance in NSCLC. • A novel albumin-bound formulation to target and modulate lipid raft integrity and cellular respiration within the TME. • Abstatin enhances T-cell infiltration and function, and reprograms the immunosuppressive landscape of NSCLC. • Abstatin significantly enhances Anti-PD-1 therapy efficacy in NSCLC models.