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REVIEW article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1643017

Glutamine Metabolism and Ammonia Death: Targeted Modulation for Enhanced Cancer Immunotherapy

Provisionally accepted
Fei DuFei Du1,2*Linlin XiaoLinlin Xiao1Wang GuojunWang Guojun1Qian DaiQian Dai1Junxin LiJunxin Li3Xin ZhaoXin Zhao1Qimin ZhangQimin Zhang1Lan YangLan Yang1Yujie LiuYujie Liu1Yidan HuYidan Hu4Bo WenBo Wen1Jingqiu ZhouJingqiu Zhou1Jie DaiJie Dai1Wenhao ZhangWenhao Zhang1Zhuo ZhangZhuo Zhang5*
  • 1Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University， Meishan, 620000, Sichuan, PR China, Meishan, China
  • 2Southwest Medical University, Luzhou, China
  • 3The Fourth People's Hospital of Zigong City, Zigong, China
  • 4The Fourth Affiliated Hospital of Southwest Medical University， Meishan, 620000, Sichuan, PR China., Meishan, China
  • 5College of Pharmacy, Southwest Medical University, Luzhou, China

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Immunotherapy has rapidly emerged as a transformative advancement in cancer treatment, becoming essential for managing diverse malignancies. Despite the remarkable clinical efficacy of immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR)-T cells, across various tumor types, patient responses remain heterogeneous, with some tumors developing resistance through immune evasion strategies. Presently, the investigation of cell death mechanisms is gaining momentum as a promising avenue for immunotherapy optimization. Recent studies underscore that integrating cell death pathways with immunotherapy can significantly amplify anti-tumor immune responses. Ammonia, a metabolic byproduct within the tumor microenvironment (TME), has garnered increasing interest. Specifically, emerging research suggests that ammonia, accumulating in effector T cells as a result of glutamine metabolism, induces cell death. This distinct form of cell death, termed "ammonia death," diverges from previously characterized mechanisms. This review examines the metabolic role of glutamine in various TME cells, explores the potential regulatory links between glutamine metabolism and ammonia-induced cell death, and evaluates the feasibility of targeting ammonia-induced cell death to enhance anti-tumor immunity and improve immunotherapy outcomes.

Keywords: ammonia death, Glutamine, CD8+ T cell, Tumor Microenvironment, Immunotherapy

Received: 07 Jun 2025; Accepted: 31 Aug 2025.

Copyright: © 2025 Du, Xiao, Guojun, Dai, Li, Zhao, Zhang, Yang, Liu, Hu, Wen, Zhou, Dai, Zhang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Fei Du, Department of Pharmacy, The Fourth Affiliated Hospital Of Southwest Medical University， Meishan, 620000, Sichuan, PR China, Meishan, China
Zhuo Zhang, College of Pharmacy, Southwest Medical University, Luzhou, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material