Enigmatic Roles of Complement Anaphylatoxin Signaling in Health and Disease

Complement anaphylatoxins C3a and C5a are potent immunomodulators whose impact extends well beyond their traditional roles in innate immunity. Acting through G protein-coupled receptors C3aR, C5aR1, and C5aR2, these peptides take part in coordinating immune cell recruitment, vascular tone, and tissue remodeling. Yet their functions are deeply context-dependent: while they play essential roles in microbial clearance and immune coordination, their overactivation contributes to immunopathology in a wide range of diseases. The anaphylatoxins play key roles in early pathogen containment but can also drive cytokine storm and tissue damage, as in coronavirus disease 2019 (COVID-19) and bacterial sepsis. In autoimmune conditions, the anaphylatoxins promote leukocyte infiltration and complement-mediated tissue injury. In chronic diseases, they contribute to fibrosis in diabetic kidney disease and idiopathic pulmonary fibrosis, and anaphylatoxins disrupt neurovascular integrity in neurodegenerative diseases. In cancer, C3a and C5a shape the tumor microenvironment by facilitating immune evasion, angiogenesis, and metastasis. As complement-targeted therapies gain momentum in clinical settings-particularly in the treatment of genetic disorders, such as paroxysmal nocturnal hemoglobinuria, more recently COVID-19, and cancer-a deeper mechanistic understanding of C3a and C5a signaling is imperative as we advance closer toward precision medicine, and this review aims to inform future approaches for therapeutic complement modulation.