PLA2G2D is a secretory, calcium-dependent phospholipase A2 that hydrolyzes phospholipids at the sn-2 position, with preference for phosphatidylethanolamines and phosphatidylcherols. In lymphoid tissues, it releases omega-3 polyunsaturated fatty acids that serve as precursors for anti-inflammatory lipid mediators such as resolvins, which suppress dendritic cell activation and Th1 responses. Beyond its catalytic function, PLA2G2D promotes regulatory T cell differentiation and immune tolerance through a mechanism independent of enzymatic activity. PLA2G2D also displays bactericidal activity against Gram-positive bacteria. Pathogenic variants in PLA2G2D associate with multiple immunodeficiency disorders and autoimmune diseases, reflecting its critical role in immune homeostasis. However, paradoxically, elevated PLA2G2D expression in aged mice during respiratory coronavirus infection worsens disease outcomes by over-suppressing dendritic cell activation and antiviral T cell responses 1. In middle-aged mice immunized against SARS-CoV, MERS-CoV, or SARS-CoV-2, PLA2G2D deficiency prevented antibody and follicular helper T cell production through pathogenic respiratory dendritic cell hyperactivation 2. In type 2 diabetes, a Pdpn+ macrophage subset employing the PLA2G2D–DHA/EPA–GPR120 pathway exhibits vascular protective effects 3. Upregulated PLA2G2D expression has been identified as a biomarker of adaptive resistance to pembrolizumab in cancer immunotherapy 4.