Nitration in cancer signaling

Oxidative stress arises from an imbalance between the production of reactive oxygen and nitrogen species (ROS and RNS, respectively) and the capacity of cellular antioxidant defenses to neutralize them. In cancer, this imbalance drives pathological remodeling of signaling networks that promote tumor initiation and progression. Among RNS, nitric oxide (·NO) and its highly reactive derivative peroxynitrite (ONOO^-) are central mediators of redox dysregulation within the tumor microenvironment. These species induce site-specific post-translational modifications (PTMs), most notably protein tyrosine nitration, which can profoundly alter protein structure, function, interaction networks, and turnover, thereby reshaping essential cellular processes. In this review, we examine the molecular mechanisms of oxidative stress with a particular emphasis on nitration-driven protein modifications and their impact on oncogenic signaling. We highlight accumulating evidence that selective nitration of key signaling proteins actively contributes to multiple hallmarks of malignancy. These nitration events promote tumor initiation and growth, aberrant proliferation, migration and metastasis, metabolic reprogramming, angiogenesis, invasion, resistance to apoptosis, and immune evasion through disruption of core signaling pathways, cell-cycle control, and cell-death programs. Collectively, these findings support an emerging paradigm in which nitrated proteins are not merely passive byproducts of oxidative stress but active effectors of tumorigenesis. We discuss the translational implications of this concept, positioning protein tyrosine nitration as a source of mechanistically defined biomarkers and therapeutic vulnerabilities. A deeper understanding of the selectivity, structural consequences, and biological impact of protein tyrosine nitration will be essential for developing innovative precision strategies to modulate redox signaling in cancer and ultimately improve clinical outcomes.