Enzyme-Instructed Photoactivatable Supramolecular Antigens on Cancer Cell Membranes for Precision-Controlled T‑Cell-Based Cancer Immunotherapy

• Published in: Nano letters 2024-06, Vol.24 (24), p.7397-7407
• Main Authors: Ding, Yinghao, Zhang, Shengyi, Li, Wei, Chen, Xiaodong, Li, Jun, Zhang, Xiangyang, Zhang, Zhenghao, Hu, Yuanbo, Yang, Zhimou, Hu, Zhi-Wen, Shen, Xian
• Format: Article
• Language: English
• ISSN: 1530-6984; 1530-6992
• DOI: 10.1021/acs.nanolett.4c01587

Cancer immunotherapies based on cytotoxic CD8+ T lymphocytes (CTLs) are highly promising for cancer treatment. The specific interaction between T-cell receptors and peptide-MHC-I complexes (pMHC-I) on cancer cell membranes critically determines their therapeutic outcomes. However, the lack of appropriate endogenous antigens for MHC-I presentation disables tumor recognition by CTLs. By devising three antigen-loaded self-assembling peptides of pY-K­(Ag)-ERGD, pY-K­(Ag)-E, and Y-K­(Ag)-ERGD to noncovalently generate light-activatable supramolecular antigens at tumor sites in different manners, we report pY-K­(Ag)-ERGD as a promising candidate to endow tumor cells with pMHC-I targets on demand. Specifically, pY-K­(Ag)-ERGD first generates low-antigenic supramolecular antigens on cancer cell membranes, and a successive light pulse allows antigen payloads to efficiently release from the supramolecular scaffold, directly producing antigenic pMHC-I. Intravenous administration of pY-K­(Ag)-ERGD enables light-controlled tumor inhibition when combined with adoptively transferred antigen-specific CTLs. Our strategy is feasible for broadening tumor antigen repertoires for T-cell immunotherapies and advancing precision-controlled T-cell immunotherapies.