Targeting triple-negative breast cancer using cord-blood CD34⁺ HSPC-derived mesothelin-specific CAR-NKT cells with potent antitumor activity

作者：Yan-Ruide Li, Xinyuan Shen, Yichen Zhu, Zhe Li, Ryan Hon, Yanxin Tian, Jie Huang, Aiqi Zhao, Y. Nathan, Catherine Zhang, David Lin, Karine Sargsyan, Yuan Yuan, Lili Yang · 发表于：Journal of Hematology & Oncology · 年份：2025 · DOI：10.1186/s13045-025-01736-9 · 被引用次数：20 · 研究领域：CAR-T cell therapy research、Immune Cell Function and Interaction、Immunotherapy and Immune Responses

Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the lack of ER, PR, and HER2 expression. Its aggressive behavior, high degree of tumor heterogeneity, and immunosuppressive tumor microenvironment (TME) are associated with poor clinical outcomes, rapid disease progression, and limited therapeutic options. Although chimeric antigen receptor (CAR)-engineered T cell therapy has shown certain promise, its applicability in TNBC is hindered by antigen escape, TME-mediated suppression, and the logistical constraints of autologous cell production. Methods In this study, we employed hematopoietic stem and progenitor cell (HSPC) gene engineering and a feeder-free HSPC differentiation culture to generate allogeneic IL-15-enhanced, mesothelin-specific CAR-engineered invariant natural killer T ( Allo15 MCAR-NKT) cells. Results These cells demonstrated robust and multifaceted antitumor activity against TNBC, mediated by CAR- and NK receptor-dependent cytotoxicity, as well as selective targeting of CD1d + TME immunosuppressive cells through their TCR. In both orthotopic and metastatic TNBC xenograft models, Allo15 MCAR-NKT cells demonstrated potent antitumor activity, associated with robust effector and cytotoxic phenotypes, low exhaustion, and a favorable safety profile without inducing graft-versus-host disease. Conclusions Together, these results support Allo15 MCAR-NKT cells as a next-generation, off-the-shelf immunothera...