A Tailor-Made Biaryl-Stapled Peptide Nanoprodrug with Esterase-Triggered Dual Immunomodulation for Amplified Cancer...

The limited immune response rate of conventional cancer monoimmunotherapy prompts the pursuit of new therapeutic modalities with improved antitumor efficacy. Here, we report a dual-immunomodulatory stapled peptide nanoassembly for amplified immunometabolic cancer therapy. This nanoprodrug platform features a biaryl-stapled proapoptotic peptide motif covalently conjugated to the indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919 via an ester bond, enabling esterase-triggered payload release within the tumors. Upon activation, the stapled peptide potently induces immunogenic cell death (ICD), while NLG919 selectively inhibits IDO, thereby reversing kynurenine-mediated immunosuppression. Notably, the stapled peptide nanoprodrug achieves prolonged local drug exposure by leveraging the enhanced proteolytic stability and cellular association conferred by the biaryl-stapling architecture. In vivo studies demonstrate that this dual-immunomodulatory strategy significantly improves the efficacy of immunotherapy when combined with PD-L1 blockade. This work paves the way to advance the development of stapled peptide-based nanoplatforms as next-generation cancer immunotherapies.