Ammonia metabolized by regulatory T cells impedes anti-tumor immunity

Tumor metabolism selectively enriches Tregs to achieve immunosuppression, but the underlying mechanisms remain unclear. 

The researchers show that tumor derived ammonia drives Treg-specific enrichment.

Tregs detoxify ammonia via the urea cycle by upregulating argininosuccinate lyase (ASL) and spermine synthesis by the FOXP3 transcription factor regulated spermine synthase (SMS), which enhances their function.

The authors also observed a direct interaction between spermine and PPAR, leading to comprehensively modulating the transcription of multiple mitochondrial complex proteins to enhance oxidative phosphorylation and immunosuppression of Tregs.

They also show that dying tumor cells treated with anti-PD-1used transdeamination to release ammonia, which reinforced Treg function, leading to immunotherapeutic resistance.

Thus, the authors suggest blocking ammonia production to suppress Tregs could be used as next-generation cancer immunotherapies.

https://www.cell.com/cell/fulltext/S0092-8674(25)01369-8
https://sciencemission.com/Tumor-produced-ammonia