pH-responsive activation of Tet-On inducible CAR-T cells enables spatially selective treatment of targeted solid tumors at reduced safety risk

作者：Yan Liu, Hao Yu, Jin Zhang, Mengmeng Zhang, Jiahui Chen, Zhengmiao Xia, Minming Chen, Xiang Lv, Xinxing Ma, Yehui Zhou, Jing Xu, Linqi Zhu, Wei Zhou, Liangzhu Feng · 发表于：National Science Review · 年份：2025 · DOI：10.1093/nsr/nwaf306 · 被引用次数：5 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Cancer Research and Treatments

ABSTRACT Chimeric antigen receptor T (CAR-T)-cell therapy is a promising resolution for solid tumors, but its corresponding clinical translation has been hindered by unsatisfactory therapeutic potency and severe cytokine release syndrome. Herein, tetracycline (Tet)-On inducible human epidermal growth factor receptor 1 (HER1)-targeted CAR-T (Tet-HER1-CAR-T) cells were engineered to enable spatially selective activation at tumor sites by doxycycline (Doxy), which is delivered by pH-responsive stealth liposomal calcium carbonate nanoparticles (Doxy@CaCO3-PEG). Compared with the intravenous administration of conventional HER1-CAR-T cells and Tet-HER1-CAR-T cells activated by free Doxy, concurrent intravenous administration of Tet-HER1-CAR-T cells and Doxy@CaCO3-PEG leads to the localized tumor activation of Tet-HER1-CAR-T cells and reduced systemic secretion of inflammatory cytokines. Together with its ability to protect Tet-HER1-CAR-T cells from tumor-acidity-induced dysfunction by neutralizing tumor acidity, Doxy@CaCO3-PEG injection synergized with Tet-HER1-CAR-T cells to effectively suppress the growth of HER1-overexpressing subcutaneous triple-negative breast cancer (TNBC) tumors, lung tumors and orthotopic lung tumors in mice. Furthermore, Doxy@CaCO3-PEG-activated Tet-HER1-CAR-T-cell therapy synergistically suppressed HER1 inhibitor-resistant TNBC tumors and immunosuppressive Fusobacterium nucleatum (F.n.) colonized HER1-overexpressing TNBC patient-derived tumor xenografts. ...