Dynamic reprogramming of the tumor immune network via multicycle checkpoint degradation for cancer immunotherapy
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Tao Shi
School of Chemistry, Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi’an Key Laboratory of Sustainable Energy Materials Chemistry
Yuanyuan Wu
Beijing Supracirc Biotechnology CO. LTD, 201, Floor 2, Building 2, Yiyuan District B, No. 80 Xingshikou Road, Haidian, Beijing 100195, China
Yiran Cai
Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
Yuting Luo
Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
Shiji Ren
Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
Yaning Cao
Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
Yin Tang
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
Zizheng Jiang
Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
Shiyao Hu
Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
Wenxue Xie
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
Yuanyuan Chen
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
Lin Shen
Hang Xing
State Key Laboratory of Chemo-/Bio-Sensing and Chemometrics, School of Chemistry and Chemical Engineering
Jia Wei
State Key Laboratory of Microbial Technology, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University