Donor Substitution Engineering of Hemicyanine Nanoparticles to Reprogram the Tumor Microenvironment and Enhance Fn14‐Targeted BiTE for Glioblastoma Photoimmunotherapy

Abstract Glioblastoma (GBM) is a highly malignant intracranial tumor with limited treatment options. Bispecific T‐cell engagers (BiTEs) are being explored for GBM treatment, but their success is hindered by inadequate T cell infiltration and activation due to the acidic and immunosuppressive microenvironment. Photothermal immunotherapy lyses tumors and activates immune responses, complementing BiTEs. This study innovatively employs a donor engineering strategy to develop hemicyanine dyes (Hcys) that emit from near‐infrared (NIR) I to NIR II. The Hcy with excellent properties is encapsulated in an amphiphilic micelle, forming a nano assembly with lactate oxidase (PLH1100). PLH1100 exhibits spectral absorption at 980 nm, a photothermal conversion efficiency of 58.7%, and capability for NIR‐II tumor imaging. Besides photothermal tumor ablation, PLH1100 regulates lactic acid metabolism and activates immunogenic cell death, improving the tumor microenvironment and promoting T cell infiltration and activation. Further studies demonstrate PLH1100 effectively kills human and murine GBM cells, inhibits orthotopic U87 tumor growth in BALB/c‐nu mice, and enhances the efficacy of Fn14‐targeted BiTE in orthotopic GL261 tumors in C57BL/6 mice, achieving a synergistic “1+1>2” therapeutic effect. Collectively, this work opens a new pathway for using Hcy‐based molecules combined with BiTE drugs for GBM therapy, with significant clinical potential.