Ammonia metabolic reprogramming in the tumor microenvironment: emergence of an immunosuppressive niche

Metabolic reprogramming within the tumor microenvironment plays a pivotal role in tumor proliferation, progression, and immune evasion. Cancer cells exhibit altered lipid, glucose, and amino acid metabolism to adapt to hostile conditions such as hypoxia and nutrient deprivation. Particularly, ammonia metabolism has emerged as a critical aspect of tumor metabolic reprogramming. Oncogene mutations, such as those in c-MYC, KRAS, and p53, regulate key enzymes involved in amino acid metabolism, which in turn affects tumor cell survival and proliferation. Elevated ammonia levels in the TME (Tumor Microenvironment) not only provide essential nitrogen for cell growth but also impair immune cell function, including T cells and natural killer cells, contributing to immune evasion. High ammonia concentrations suppress T cell activation and promote exhaustion, while interfering with natural killer cell cytotoxicity by hindering perforin maturation. Moreover, ammonia accumulation fosters an immunosuppressive microenvironment, influencing cytokine secretion and facilitating tumor metastasis. Targeting ammonia metabolism, in combination with immune checkpoint inhibitors, presents a promising therapeutic strategy to enhance immune responses and inhibit tumor progression. This review consolidates recent findings on the role of ammonia metabolism in the TME, highlighting its potential as a therapeutic target to improve cancer treatment outcomes.