Self-reinforcing nanoplatform uniting pemetrexed, magnetic hyperthermia and PD-L1 blockade reshapes the tumor microenvironment and elicits combined antitumor immunity in lung adenocarcinoma

Lung cancer remains the leading cause of cancer-related mortality worldwide, and immune checkpoint blockade is often limited by an immunosuppressive tumor microenvironment (TME). To address these challenges, we developed a novel multifunctional nanoplatform, based on a mesoporous Fe 3 O 4 core and silica shell, co-loading pemetrexed and an anti-PD-L1 antibody (PD-L1&Pem@msNPs). The construct enables checkpoint-targeted delivery, alternating magnetic field (AMF)-triggered hyperthermia and controlled drug release, enabling a single-system chemo–immuno–magnetothermal regimen. We comprehensively investigated the physicochemical properties, magnetothermal performance, loading/conjugation, and release behavior, and validated cellular uptake and cytotoxicity in vitro. In subcutaneous and orthotopic lung tumor models, PD-L1&Pem@msNPs achieved superior tumor suppression and extended survival compared with control formulations. Mechanistically, transcriptomic profiling together with immunophenotyping demonstrated marked TME remodeling, with increased intratumoral T-cell representation accompanied by coordinated rewiring of macrophages status. Notably, longitudinal flow cytometry revealed a shift in T-cell states from an exhausted-intermediate (Tex-int) toward a progenitor-like (Tex-prog) phenotype, consistent with restoration of T-cell functionality under treatment. Collectively, PD-L1&Pem@msNPs provides an externally activatable, modular platform to remodel the TME and improve the therapeutic impact of PD-L1 blockade in lung cancer. • Magnetothermal-chemo-PD-L1 platform enhances target release and immunogenicity. • Reverses the T cell exhaustion and remodels the immunosuppressive TME. • Tumor-targeted co-delivery achieves strong antitumor efficacy and limited toxicity.