Immune-driven remodeling in calcific aortic valve disease: mechanisms and immunotherapeutic opportunities

Calcific aortic valve disease (CAVD) is a prevalent degenerative valvular disorder in the aging population, for which no pharmacological therapy has proven effective in halting or reversing disease progression. Over the past decade, CAVD has been increasingly recognized not as a passive degenerative process of calcium deposition, but as an active, inflammation-driven disease characterized by osteogenic remodeling. This process is initiated and sustained by endothelial injury, lipid retention, immune cell infiltration, and phenotypic transition of valvular interstitial cells. Growing evidence indicates that innate and adaptive immune responses may contribute to disease amplification. Innate immune cells propagate local inflammatory signaling through inflammasome activation, extracellular vesicle communication, protease release, and neutrophil extracellular trap formation, while adaptive immune cells further shape disease progression by sustaining cytokine networks that promote fibrosis and osteogenic reprogramming within the valvular microenvironment. Based on these mechanistic insights, this review further discusses emerging translational strategies aimed at targeting key pathogenic processes in CAVD, including modulation of inflammatory signaling, restoration of adaptive immune homeostasis, regulation of extracellular matrix remodeling and antifibrotic pathways, inhibition of VIC osteogenic differentiation, as well as development of patient stratification and local drug delivery approaches. Collectively, these strategies may provide a conceptual framework for earlier, non-surgical interventions for CAVD.