Immune checkpoint blockade (ICB) therapy, while achieving tremendous clinical successes, still suffers from a low objective response rate in clinical cancer treatment. As a proof-of-concept study, we propose a new immune checkpoint degradation (ICD) therapy relying on lysosome-targeting chimera (LYTAC) to deplete immune checkpoint programmed death ligand-1 (PD-L1) on the tumor cell surface. Our designed chimeric aptamer on one side targets lysosome-trafficking receptor, and on the other side allows biorthogonal covalent-conjugation-reinforced specific binding of PD-L1. This covalent LYTAC is able to hijack PD-L1 for lysosomal degradation with greatly improved efficiency over its noncovalent counterpart in complex in vivo environment. Beyond abolishing the PD-1/PD-L1 axis associated immune resistance, we demonstrate for the first time that LYTAC-triggered PD-L1 degradation could directly cause immunogenic apoptosis of tumor cells to elicit tumor-specific immune responses, offering unparalleled advantages over ICB antibody therapy. Remarkably, ICD therapy with covalent LYTAC achieves comparable or higher antitumor efficacy while causing significantly less inflammatory injury compared to antibody-based ICB therapy. Moreover, covalent LYTAC can serve as a general platform for specifically degrading other membrane-associated proteins, making it a promising tool for future applications. Our work presents a novel molecular tool for effective LYTAC in complex environments, offering valuable insights in pushing DNA-based LYTAC drugs toward in vivo and clinical applications.