The research examined the molecular mechanisms through which ammonia causes CD8 + T-cell death. The study’s key finding indicates that ammonia induces toxicity through the impairment of two essential organelles: lysosomes and mitochondria. Lysosomes function to degrade and recycle cellular waste, thereby maintaining cellular homeostasis. The research demonstrated that ammonia directly compromises the lysosomal membranes of CD8 + T cells, resulting in the leakage of degradative enzymes into the cytoplasm. Lysosomal damage is a critical event that initiates a series of detrimental intracellular reactions, ultimately resulting in cell death. The researchers identified that ammonia is transported into lysosomes through a specific transporter known as Rhesus glycoprotein C (RHCG). This study elucidates the molecular mechanism by which ammonia is transported into lysosomes and identifies a potential therapeutic target for inhibiting this process, thus safeguarding T cells from ammonia-induced toxicity. The study revealed that when lysosomes are unable to absorb ammonia, excess ammonia accumulates in other cellular regions, particularly in the mitochondria. Mitochondria, known as the cell’s energy powerhouse, exhibit significant sensitivity to metabolic disruptions. The accumulation of ammonia within mitochondria results in dysfunction, which induces oxidative stress, diminishes membrane potential, and ultimately leads to cell death [6]. The dual mechanism by which ammonia induces damage to lysosomes and mitochondria underscores the complex toxic effects of ammonia on effector CD8 + T cells. Understanding the mechanisms by which ammonia disrupts lysosomal and mitochondrial functions enables researchers to investigate strategies for mitigating this damage and prolonging T-cell lifespan.

Autophagy is essential for the removal of damaged mitochondria in the context of ammonia-induced damage [7]. The study indicates that mitochondrial damage resulting from ammonia is excessively severe for autophagy to adequately eliminate, resulting in the accumulation of impaired mitochondria and worsening cellular dysfunction and mortality. The impairment of autophagy suggests that ammonia not only directly harms organelles but also diminishes the cell’s capacity to repair such damage, thereby hastening cell death. This discovery introduces a novel therapeutic strategy: enhancing autophagy or expediting the removal of damaged organelles may rescue T cells from ammonia-induced apoptosis, thus augmenting the efficacy of immunotherapy. Immune “cold” tumors often exhibit poor responses to immunotherapy due to inadequate immune cell infiltration. Regulating ammonia metabolism may enhance T-cell survival within these microenvironments and increase their infiltration, thereby improving therapeutic efficacy against immune “cold” tumors. Future research could further explore the effects of ammonia metabolism modulation on different types of tumors, particularly those that respond poorly to conventional immunotherapies.

This study’s primary significance is its potential for clinical translation. The study indicated that inhibiting ammonia-induced cell death can markedly improve the effectiveness of adoptive T-cell therapy. Currently, several ammonia-clearing agents, such as sodium benzoate, sodium phenylbutyrate, and glycerol phenylbutyrate, are utilized in clinical or experimental settings due to their efficacy in reducing ammonia levels in the body. Common side effects associated with these agents include mild allergic reactions, nausea, and abdominal pain. A comprehensive evaluation of the efficacy and safety of these products is essential for developing more effective treatment strategies for patients. In preclinical cancer models, researchers demonstrated that inhibiting ammonia accumulation or mitigating its toxic effects can prolong the survival of CD8 + T cells and improve their functionality [8,9,10]. The findings indicate that targeting ammonia metabolism could serve as a new approach to enhance the durability and efficacy of cancer immunotherapy. This discovery provides potential solutions for a significant challenge in contemporary immunotherapies: the restricted longevity of effector T cells. Preventing ammonia-induced cell death may extend T-cell lifespan within the tumor microenvironment, leading to enhanced antitumor activity. This strategy may be integrated with current immunotherapies, including immune checkpoint inhibitors or CAR-T-cell therapy, to enhance synergistic effects and optimize patient outcomes (Table 1).