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

Abstract

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.