A Standalone PD-1 Chimeric Switch Receptor T-Cell Platform Expands the Therapeutic Window of PD-L1 Targeting in Solid Tumors

Programmed death-ligand 1 (PD-L1) is a promising therapeutic target owing to its broad expression on tumor cells and immunosuppressive myeloid cells within the tumor microenvironment (TME), providing an opportunity to target both cellular compartments. However, physiological PD-L1 expression in normal tissues poses a substantial risk of on-target/off-tumor toxicity, limiting the therapeutic window and clinical translation of PD-L1-targeted cellular therapies. Here, we developed a standalone programmed death-1 (PD-1) chimeric switch receptor (CSR) T-cell platform designed to preserve the therapeutic advantages of PD-L1 targeting while improving tumor-normal discrimination. Iterative receptor engineering, with antitumor activity and normal-cell reactivity evaluated as parallel selection criteria, identified two lead PD-1 CSR T-cell candidates. Compared with our previously developed antibody-based PD-L1 CAR T cells, the lead candidates retained potent PD-L1-specific cytotoxicity against tumor cells while exhibiting markedly reduced cytotoxicity against primary human small airway epithelial cells, astrocytes, renal epithelial cells, hepatocytes, and cardiomyocytes. They also efficiently eliminated PD-L1-positive immunosuppressive myeloid cells and mediated dual-compartment targeting of tumor and myeloid cells in three-dimensional (3D) multicellular tumor organoids. In vivo, both candidates suppressed tumor growth and prolonged survival in orthotopic breast cancer and patient-derived glioblastoma models after systemic and intracranial administration, respectively. Collectively, these findings establish PD-1 CSR T cells as a standalone therapeutic platform that expands the therapeutic window of PD-L1-targeted cellular therapy by preserving dual-compartment targeting of tumor and immunosuppressive myeloid cells while reducing normal-cell reactivity, providing a foundation for further clinical translation across solid tumors.