Nanoplatform-mediated PRMT3 inhibition synergizes cuproptosis and radiotherapy to remodel the NSCLC immune microenvironment

Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality worldwide, with therapeutic progress hindered by the immunosuppressive and heterogeneous tumor microenvironment (TME). Protein arginine methyltransferase 3 (PRMT3), a key regulator of post-translational modifications (PTMs), plays a pivotal role in immune evasion and therapeutic resistance by modulating key oncogenic and immune pathways. Despite the potential of PRMT3 inhibitors, such as SGC707, their clinical efficacy is limited by poor pharmacokinetics, inadequate therapeutic durability, and the complex interplay within the TME. To address these challenges, we developed a multifunctional nanoplatform, poly (acrylic acid)‑copper bismuth tellurium@SGC707 nanospheres (PAA-CuBiTe@SGC707 NSs), which integrates copper-induced cell death (cuproptosis), radiosensitization, and PRMT3 inhibition to achieve synergistic therapeutic outcomes. The nanoplatform induces mitochondrial DNA (mtDNA) release, thereby activating a cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-mediated immunogenic response, which is further amplified by SGC707 through the suppression of PRMT3-mediated arginine methylation of cGAS. Furthermore, the incorporation of Bi and Te nanoparticles endows the nanoplatform with effective radiosensitization capability, improving the precision and efficacy of radiotherapy. This study presents a novel nanotechnology-driven therapeutic strategy that simultaneously addresses immune resistance and radiotherapy limitations, providing a promising approach for improving NSCLC treatment outcomes.