PLA2G2D (phospholipase A2 group IID) is a secretory calcium-dependent phospholipase A2 that hydrolyzes phospholipids to generate lipid mediators with complex immunomodulatory functions. The enzyme exhibits anti-inflammatory properties by releasing omega-3 polyunsaturated fatty acids that serve as precursors for pro-resolving mediators like resolvins 1. However, PLA2G2D also demonstrates context-dependent pro-inflammatory effects. In respiratory infections, age-related increases in PLA2G2D expression contribute to worse outcomes by impairing dendritic cell function and T cell responses, with knockout mice showing dramatically improved survival rates (>80% vs. uniformly lethal) against SARS-CoV 2. The enzyme also plays a detrimental role in cancer immunotherapy by promoting immune escape through upregulation of PD-L1-expressing extracellular vesicles, which inhibit CD8+ T cell function and cytokine production 3. Additionally, PLA2G2D shows elevated expression in COVID-19 and other severe respiratory conditions, correlating with disease severity 4. A Gly80Ser polymorphism enhances cytokine inducibility, potentially explaining weight loss in COPD patients carrying this variant 5. These findings highlight PLA2G2D's dual nature as both an anti-inflammatory mediator and a factor that can impair protective immune responses in specific disease contexts.