Akhtar Areej, Shakir Md, Ansari Mohammad Sufyan, Faizan Md Imam, Chauhan Varnit, Singh Aashi, Alam Ruquaiya, Azmi Iqbal, Sharma Sheetal, Pracha Mehak, Uddin Insha Mohi, Bashir Uzma, Shahni Syeda Najidah, Chaudhuri Rituparna, Albogami Sarah, Ganguly Rik, Sagar Shakti, Singh Vijay Pal, Kharya Gaurav, Srivastava Amit Kumar, Mabalirajan Ulaganathan, Roy Soumya Sinha, Rahman Irfan, Ahmad Tanveer
Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia, New Delhi, India.
Indian Institute of Science, Centre for Brain Research, Bengaluru, Karnataka, India.
Cell Rep Med. 2025 Mar 18;6(3):102021. doi: 10.1016/j.xcrm.2025.102021.
Constant tumor antigen exposure disrupts chimeric antigen receptor (CAR) T cell metabolism, limiting their persistence and anti-tumor efficacy. To address this, we develop metabolically reprogrammed CAR (MCAR) T cells with enhanced autophagy and mitophagy. A compound screening identifies a synergy between GLP-1R agonist (semaglutide [SG]) and Urolithin A (UrA), which activate autophagy through mTOR (mechanistic target of rapamycin) inhibition and mitophagy via Atg4b activation, maintaining mitochondrial metabolism in CAR T cells (MCAR T-1). These changes increase CD8 T memory cells (Tm), enhancing persistence and anti-tumor activity in vitro and in xenograft models. GLP-1R knockdown in CAR T cells diminishes autophagy/mitophagy induction, confirming its critical role. We further engineer GLP-1-secreting cells (MCAR T-2), which exhibited sustained memory, stemness, and long-term persistence, even under tumor re-challenge. MCAR T-2 cells also reduce cytokine release syndrome (CRS) risks while demonstrating potent anti-tumor effects. This strategy highlights the potential of metabolic reprogramming via targeting autophagy/mitophagy pathways to improve CAR T cell therapy outcomes, ensuring durability and efficacy.
持续的肿瘤抗原暴露会破坏嵌合抗原受体（CAR）T细胞的代谢，限制其持久性和抗肿瘤功效。为了解决这一问题，我们开发了具有增强自噬和线粒体自噬功能的代谢重编程CAR（MCAR）T细胞。一项化合物筛选确定了胰高血糖素样肽-1受体（GLP-1R）激动剂（司美格鲁肽[SG]）和尿石素A（UrA）之间的协同作用，它们通过抑制雷帕霉素靶蛋白（mTOR）激活自噬，并通过激活Atg4b促进线粒体自噬，维持CAR T细胞（MCAR T-1）的线粒体代谢。这些变化增加了CD8 T记忆细胞（Tm），增强了体外和异种移植模型中的持久性和抗肿瘤活性。CAR T细胞中的GLP-1R基因敲低减少了自噬/线粒体自噬的诱导，证实了其关键作用。我们进一步构建了分泌GLP-1的细胞（MCAR T-2），即使在肿瘤再次攻击的情况下，该细胞也表现出持续的记忆、干性和长期持久性。MCAR T-2细胞还降低了细胞因子释放综合征（CRS）的风险，同时显示出强大的抗肿瘤作用。这一策略突出了通过靶向自噬/线粒体自噬途径进行代谢重编程以改善CAR T细胞治疗效果的潜力，确保了治疗的持久性和有效性。
