Clickable Universal Tumor-Antigen Equipping Strategy for Remedial Chimeric Antigen Receptor T Cells to Destroy Solid Tumors.

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has shown striking efficacy in leukemia and lymphoma, but solid tumors remain largely refractory due to the scarcity of tumor-specific antigens and pervasive antigen heterogeneity, compounded by rapid CAR-T cell exhaustion that curtails their function and persistence. Here, we propose a clickable universal tumor-antigen equipping (CUTE) strategy in which exogenous antigen is modularly clicked onto the tumor cell surface by metabolic glycoengineering (MGE), remodeling the landscape of tumor antigens. The CUTE strategy yielded a 5.7-fold higher antigen density than endogenous CD19 on Raji cells and markedly increased the functional avidity of CAR-T cells in vitro. The resulting high antigen density stabilized CAR conformations, prevented scFv aggregation-driven tonic signaling, and consequently reduced the exhaustion of CAR-T cells. In both cell-derived and patient-derived xenograft (CDX and PDX) models, the CUTE strategy conferred remedial therapeutic efficacy of CAR-T cells against tumors, significantly prolonging overall survival, with no added toxicity observed. Thus, the CUTE strategy provides a modular platform for redirecting clinically validated CAR-T cells to any solid tumor and offers a potentially translatable route to extend CAR-T therapy beyond hematological cancers.