Chi et al. engineered a recyclable PD-L1 degrader (RECYC) by fusing a moderate-affinity peptide binder of PD-L1 to an aptamer against the ubiquitous endolysosomal trafficking receptor CI-M6PR. RECYC robustly degraded PD-L1 in tumor and myeloid cells, and exhibited pH-sensitive dissociation from PD-L1, enabling repeated knockdown following membrane recycling. I.v. RECYC outperformed anti-PD-L1 in multiple tumor models. and drove greater PD-L1 knockdown in tumor and myeloid cells, which correlated with efficacy. RECYC enhanced T cell infiltration and early activation, and uniquely promoted M1/N1-like skewing in tumor-associated macrophages and neutrophils.
Contributed by Morgan Janes
ABSTRACT: The efficacy of immune checkpoint blockade is often limited by intrinsic immunosuppressive networks within the tumor immune microenvironment (TIME). Despite progress in cancer treatment, current extracellular targeted protein degradation approaches often overlook the multicellular distribution and crosstalk of immune checkpoints. Here we reported a Receptor-mediated Endolysosomal recYcling Chimera (RECYC) platform. RECYC employs a CI-M6PR-targeting aptamer that remains stable across late endosomal pH and a protein-binding peptide with moderate affinity and pH responsiveness, which together drive recycling and sustained checkpoint clearance. In ex vivo co-culture and in vivo murine models, RECYC efficiently eliminated programmed death-ligand 1 (PD-L1) expression from both tumor cells and tumor-associated myeloid cells (macrophages, neutrophils and dendritic cells). By converting an immunosuppressive TIME to an immunostimulatory state, RECYC remodeled the tumor-immune network in an anti-tumor direction, thereby enhancing CD8(+) T cell response and repolarizing immunosuppressive myeloid cells. Moreover, in both immune-cold and immune-hot murine cancer models, RECYC demonstrated superior anti-tumor effect compared to PD-L1 blockade treatment. Collectively, we propose an effective strategy to induce recycling and broad checkpoint clearance in the TIME, which in turn reprograms the multicellular tumor-immune network to achieve durable immunotherapy responses.
Author Info: (1) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (2) Institute of Chemical Biology and Nan
Author Info: (1) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (2) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (3) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (4) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (5) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (6) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (7) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (8) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (9) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (10) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (11) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (12) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (13) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (14) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing 210061, China. Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.
