TCR-mimicking STAR conveys superior sensitivity over CAR in targeting tumors with low-density neoantigens
Daosheng Huang, Yi Li, Dongmei Yang, Keyong Sun, Zhixiao Zhou, Xinping Lv, Yu Li, Junfan Chen, Jing Zhou, Vincent Liu, Jiasheng Wang, Xun Lan, Yang-Xin Fu, Xueqiang Zhao, Xin Lin
Abstract
Targeting tumor-specific neoantigens holds promise for cancer immunotherapy, but their ultra-low expression on tumor cells poses challenges for T cell therapies. Here, we found that chimeric antigen receptors (CARs) exhibit 10–100 times lower sensitivity than T cell receptors (TCRs) when targeting human leukocyte antigen (HLA) class I-presented p53 R175H neoantigen. To enhance CAR functionality, we introduced T cell receptor fusion constructs (TRuCs) and synthetic TCRs and antigen receptors (STARs). Our data show that STARs optimally reproduce TCR antigen sensitivity, outperforming CARs and TRuCs in redirecting CD8 + and CD4 + T cells to recognize HLA class I neoantigens. STAR-T cells demonstrate superior killing of cancer cell lines with low neoantigen density in vitro and improved tumor control in mouse models compared to CAR-T and TRuC-T cells. These findings highlight CAR sensitivity limitations and present STARs as more effective synthetic receptors for T cell-based immunotherapy against tumors with low neoantigen density.