Advancing targeted protein degradation: pLIRTAC's role in glioma and CAR-T cell therapy

The rapid development of targeted protein degradation (TPD) has shown profound effects on disease treatment. Precise and effective targeted degradation tools that target endogenous proteins are essential to accelerate advances in treatment methods. Selective macroautophagy/autophagy relies on the activity of related receptors to achieve the degradation of specific intracellular components in lysosomes, but the methodology of selective autophagy for tumor therapy and chimeric antigen receptor (CAR)-T cell modification is yet unexplored. Here, we developed a peptide-based LC3-interacting region-targeting chimera (pLIRTAC) that accurately and efficiently targeted the degradation of AKT1 for glioma treatment. pLIRTAC could also inhibit the development of tumor cells by in vitro delivery after purification. For CAR-T cell therapy, pLIRTAC could significantly improve the efficacy of CAR-T cell-targeted lysis of tumor cells both in vitro and in vivo. pLIRTAC binds to autophagy-associated proteins through LC3-interacting region (LIR) motifs and to target proteins through protein-targeting short peptides, and targets the protein of interest (POI) based on the selective autophagy lysosomal pathway. pLIRTAC has been remarkably successful both in vivo and in vitro, providing a robust and effective tool for the control of endogenous abnormal proteins in cells, and can potentially further expand the therapeutic application of TPD technology.Abbreviation: ATG8s: mammalian Atg8 (autophagy related 8)-family proteins; Baf-A1: bafilomycin A₁; CAR: chimeric antigen receptor; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; EBSS: Earle's balanced salt solution; LIR: LC3-interacting region; 3 MA: 3-methyladenine; MFI: mean fluorescence intensity; pLIRTAC: peptide-based LC3-interacting region-targeting chimera; POI: protein of interest; PROTAC: proteolysis-targeting chimera; SARS: selective autophagy receptors; TPD: targeted protein degradation.