Efficiently Reversing Immunotherapy Resistance in Lung Cancer by an Inhalable 2D Molybdenum Disulfide T Cell Hyperactivation Platform

Immunotherapy has revolutionized the treatment of lung cancer, but many patients still experience inadequate responses or develop resistance, emphasizing the urgent need for more effective therapeutic strategies. Here, we present the design of an inhalable flexible 2D molybdenum disulfide (MoS₂) T cell hyperactivation platform (2D MoS₂-THP) based on anchoring therapeutic proteins onto the surface of metallic molybdenum disulfide. By loading IL2 and anti-PD1 proteins onto a flexible metallic molybdenum disulfide crystalline form, we achieved effective T cell hyperactivation. Our platform leverages the synergistic effects of anti-PD1 and IL2 to remodel exhausted T cells while simultaneously overcoming regulatory T cell (Treg)-mediated immunosuppression, resulting in a superior T cell activation. Additionally, 2D metallic MoS₂ not only serves as a carrier for delivering therapeutic proteins but also plays a pivotal functional role by inducing cuproptosis in Tregs through disruption of mitochondrial function and elevation of oxidative stress, thereby clearing a key barrier to effector T cell activation. The inhalation administration route further improves intratumoral accumulation, enhances therapeutic potency, and minimizes systemic immune-related side effects. Overall, this inhalable "three-in-one" immunotherapy platform achieves robust T cell hyperactivation with reduced systemic toxicity, efficiently removing immunosuppressive barriers, and remodeling the tumor immune microenvironment to overcome cancer immunotherapy resistance.