Senescent macrophages drive squamous cell carcinoma invasion via glutamine metabolism and IL-1β/NF-κB signaling

Squamous cell carcinoma (SCC), a prevalent cancer, faces significant challenges due to its invasive potential, often driven by the complex tumor microenvironment (TME). Oxidative stress is a known TME remodeler, inducing cellular senescence and metabolic shifts. While glutamine is crucial for oxidative stress defense and TME dynamics, its precise role in initiating tumor invasion remains poorly understood. Current therapies often struggle with TME heterogeneity and resistance mechanisms, highlighting the need for novel targets that address fundamental drivers of invasion, such as metabolic reprogramming within senescent cells.

Researchers investigated the role of senescent macrophages in SCC invasion. They established cisplatin- and radiation-induced senescent macrophage models, analyzing their distinct senescence-associated secretory phenotypes (SASP). Clinical samples were examined to correlate senescent macrophage accumulation with malignancy. Integrated metabolomic and transcriptomic analyses were performed on these models to identify key metabolic pathways. The study then explored the mechanistic link between secreted factors from senescent macrophages and SCC cell migration and invasion, using in vitro assays and pathway analysis.

Oxidative stress consistently induced the generation of senescent macrophages within the TME, with their accumulation positively correlating with malignancy in clinical samples. Both cisplatin- and radiation-induced senescent macrophage models exhibited distinct SASP profiles and significantly enhanced SCC migration and invasion. Integrated metabolomic and transcriptomic analyses revealed the glutamine-glutamate pathway as a central metabolic hub, showing glutaminase 2 (GLS2) was consistently upregulated, driving glutaminolysis. This upregulation of GLS2 was 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. This IL-1β-mediated NF-κB activation was critical for the observed invasive phenotype. >Targeting the glutamine metabolism-regulated IL-1β/IL-1R2 axis effectively suppressed SCC invasion, demonstrating a direct therapeutic vulnerability.