C5AR2 (complement C5a receptor 2), also known as C5L2 or GPR77, is a G protein-coupled receptor that binds C5a and its dearginated forms (C5adesArg, C3adesArg, C4adesArg) 123. Unlike the proinflammatory C5aR1, C5AR2 primarily functions as an immune-dampening receptor 4. Mechanistically, C5AR2 activation broadly suppresses innate immune signaling by dampening ERK phosphorylation and calcium mobilization triggered by C5aR1, C3aR, and other pattern recognition receptors 5. C5AR2 also downregulates TLR- and C-type lectin receptor-mediated cytokine production, with particularly potent inhibition of Mincle-driven IL-6 and TNF-α generation 5. In adaptive immunity, C5AR2 promotes Th1 cell contraction by orchestrating a shift from prostaglandin E2 to prostacyclin production, enabling IL-1R2-mediated sequestration of IL-1β 6. Pathologically, C5AR2 downregulation has been associated with inflammatory diseases including thoracic aortic aneurysms and bullous pemphigoid, where reduced C5AR2 expression tips the inflammatory balance toward C5aR1-mediated responses 78. In cancer, CD10+GPR77+ carcinoma-associated fibroblasts drive chemoresistance via complement-mediated NF-κB signaling, suggesting C5AR2 blockade as a potential therapeutic strategy 9.