Ammonia‐Induced Cell Death: A Novel Frontier to Enhance Cancer Immunotherapy

ABSTRACT Cancer immunotherapy has revolutionized treatment paradigms, but its efficacy is often curtailed by T‐cell exhaustion and the suppressive tumour microenvironment. Recent studies reveal a novel mechanism of T‐cell demise termed ammonia‐induced cell death (AICD), which significantly impacts effector CD8+ T‐cell survival and function. This phenomenon arises from metabolic reprogramming during immune activation, wherein heightened glutamine metabolism leads to the accumulation of toxic ammonia levels. Ammonia damages lysosomes and mitochondria, disrupting cell balance and causing apoptosis. These insights provide a unique metabolic perspective on T‐cell attrition, underscoring the critical interplay between metabolic byproducts and immune regulation. Targeting AICD offers promising therapeutic avenues to bolster immunotherapy. Strategies such as inhibiting ammonia transport, enhancing autophagic pathways and employing ammonia scavengers may extend T‐cell longevity and improve antitumor efficacy. Moreover, integrating ammonia modulation with established immunotherapies, including immune checkpoint inhibitors and chimeric antigen receptor (CAR) T‐cell therapy, could yield synergistic benefits. Addressing this metabolic bottleneck is particularly compelling in immune ‘cold’ tumours resistant to conventional therapies. However, further research is essential to refine these interventions, evaluate safety profiles and explore broader applications across cancer types. Ammonia metabolism thus represents a transformative frontier in advancing cancer immunotherapy and precision oncology.