Oxidative Stress Induced Senescent Macrophage‐Driven Squamous Cell Carcinoma Invasion via Glutamine Metabolic Reprogramming

ABSTRACT

Oxidative stress drives tumor microenvironment (TME) remodeling by inducing metabolic reprogramming and cellular senescence. Glutamine, a key substrate supporting oxidative stress defense, has been implicated in TME remodeling and metastasis, yet its specific role in initiating tumor invasion remains unclear. Here, oxidative stress induced the generation of senescent macrophages in the TME, and clinical samples showed that their accumulation positively correlates with malignancy. We established cisplatin‐ and radiation‐induced senescent macrophage models that exhibited distinct senescence‐associated secretory phenotypes (SASP) and enhanced squamous cell carcinoma (SCC) migration and invasion. Integrated metabolomic and transcriptomic analyses revealed the glutamine–glutamate pathway as a central metabolic hub, with glutaminase 2 upregulated to drive glutaminolysis and strongly associated with IL‐1β expression. Mechanistically, IL‐1β secreted by senescent macrophages promoted tumor invasion by downregulating IL‐1R2 and activating NF‐κB signaling in SCC cells. Targeting the glutamine metabolism–regulated IL‐1β/IL‐1R2 axis effectively suppressed SCC invasion. These findings uncover a novel metabolic mechanism linking glutamine metabolism to SASP regulation and suggest a therapeutic strategy to limit SCC invasion.