C5AR2 (complement C5a receptor 2) is a G protein-coupled receptor that binds the complement activation fragment C5a and its dearginated forms, mediating immune modulation. Unlike the primarily proinflammatory C5AR1, C5AR2 functions as a pleiotropic suppressor of innate immunity. Selective C5AR2 activation in primary human macrophages dampens signaling through C5AR1, C3aR, and chemokine receptors while reducing cytokine production (IL-6, TNF-α, IL-1β) triggered by toll-like receptors, C-type lectin receptors, and the DNA sensor STING 1. C5AR2 also orchestrates CD4+ T helper 1 cell contraction by shifting lipid mediator metabolism from prostaglandin E2 to prostacyclin, which initiates IL-1 receptor type 2 expression and self-limiting Th1 responses 2. Dysregulation of C5AR2 is implicated in inflammatory pathologies. Thoracic aortic aneurysm patients show 73% downregulation of C5AR2 expression, potentially permitting excessive C5AR1-mediated inflammation 3. In contrast, C5AR2 signaling is therapeutically exploited: anti-GPR77 (C5AR2) antibody blockade of carcinoma-associated fibroblasts abolishes tumor formation and restores chemosensitivity in breast and lung cancer models 4. Recent evidence suggests that modulating the C5AR2-prostacyclin axis through prostaglandin synthase inhibition rectifies hyperactive Th1 cells in inflammatory conditions including cryopyrin-associated periodic syndromes, Crohn's disease, and rheumatoid arthritis 2, indicating potential for proresolving therapeutics targeting C5AR2.