Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity

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<sup>+</sup> 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.

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Publication Details

Journal
Cell Reports Medicine
Published
2025-03-01
DOI
https://doi.org/10.1016/j.xcrm.2025.102021
Citations
14
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
14.64

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article

Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity

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Cell Reports Medicine
CAR-T cell therapy research
14.64
article

Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity

Ulaganathan Mabalirajan, Varnit Chauhan, Soumya Sinha Roy, Iqbal Azmi, Divya Goel, A K Srivastava, Sarah Albogami, Gaurav Kharya, Mohammed Saleh Al Ansari, Rituparna Kundu Chaudhuri, Insha Mohi Uddin, Rik Ganguly, Irfan Rahman, Shakti Sagar, Sheetal Sharma, Areej Akhtar, Vijay Pal Singh, Aashi Singh, Raquib Alam, Tanveer Ahmad, Uzma Bashir, Md Shakir, Md Imam Faizan, Syeda Najidah Shahni, Mehak Pracha
article en
14 citations

Abstract

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<sup>+</sup> 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.

Cell Reports MedicineVol. 6(3)
Indraprastha Apollo Hospitals (IN), Indian Institute of Chemical Biology (IN), Institute of Genomics and Integrative Biology (IN), Taif University (SA), North Eastern Hill University (IN), University of Rochester Medical Center (US), Jamia Millia Islamia (IN)
Department of Biotechnology, Ministry of Science and Technology, India, Taif University
Good health and well-being
Openalex Percentile: Top 1%
CAR-T cell therapy research
14.64
DOIOpen Access PDFOpenAlex
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