Targeting CAF-induced oxidative phosphorylation in Dll4+ leader cells with injectable BZA-loaded MPDA hydrogel suppresses collective invasion in salivary adenoid cystic carcinoma.

Collective invasion is crucial for the progression and metastasis of salivary gland adenoid cystic carcinoma (SACC), but the cellular metabolic programs that are associated with leader cells remain poorly defined. Here, fluorescence-activated cell sorting isolated Dll4+ and Dll4- SACC subpopulations, and transcriptomic analysis identified oxidative phosphorylation (OXPHOS) as a prominent pathway underlying the invasive capacity of Dll4+ leader cells. COX17, a key regulator of mitochondrial complex IV (CIV) activity, was significantly upregulated in Dll4+ leader cells, supporting the importance of OXPHOS in collective invasion. CAF-derived IL-6 activated gp130 signaling in Dll4+ leader cells, enhancing OXPHOS and driving both invasion and metastasis. Furthermore, we developed an injectable hydrogel system for the local delivery of bazedoxifene acetate (BZA), a gp130 signaling inhibitor, which effectively suppressed tumor growth in an orthotopic parotid SACC model. Together, these findings reveal a CAF-IL-6/gp130-COX17/OXPHOS axis that drives Dll4-mediated collective invasion and suggest that targeting this pathway may provide a therapeutic strategy to limit SACC progression and metastasis.