Ammonia-induced cell death: A novel immunometabolic vulnerability for cancer therapy

Abstract

Ammonia, a by-product of glutamine metabolism, has emerged as a key immunometabolic regulator in the tumor microenvironment. Recent studies reveal that excessive ammonia accumulation impairs effector CD8⁺ T cell viability through a distinct form of organelle-centered cell death, characterized by lysosomal alkalinization, mitochondrial dysfunction, and autophagy inhibition. This phenomenon, termed ammonia-induced cell death (AICD), contributes to immune suppression and tumor progression. Here, we comprehensively review the molecular pathways governing ammonia production, transport, and detoxification, with a focus on the roles of GLS1, CPS1, Rh-family transporters, and associated solute carriers. We further highlight advances in chemical biology tools—such as ammonia-sensitive probes and isotope-labeled metabolomics—that enable the functional dissection of ammonia metabolism in immune and tumor cells. Emerging therapeutic strategies that combine ammonia metabolism modulators with immune checkpoint inhibitors offer promising avenues to enhance anti-tumor immunity. Despite recent progress, key challenges remain, including the incomplete understanding of ammonia clearance in T cells, limited data on other immune cell types, and concerns about metabolic toxicity. Targeting AICD thus represents a chemically tractable and clinically relevant approach at the interface of metabolism, immunity, and cancer therapy.

Keywords

Ammonia-induced cell death / Tumor microenvironment / Immunotherapy / Immune evasion / Metabolism

Funding

None.

Conflict of interest

The authors declare that they have no competing interests.

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