The Pleiotropic Effect of Complement C5a-C5aR1 Pathway in Diseases: From Immune Regulation to Targeted Therapy.

The complement system plays a pivotal role in the body's immune defense mechanism. Its key effector molecule C5a and its primary receptor C5aR1 exhibit complex "double-edged sword" effects in various disease processes, including infectious diseases, inflammatory conditions, tumors, and metabolic disorders. Under normal physiological conditions, moderate levels of C5a bind to the C5aR1 receptor, recruiting immune cells to the site of infection to participate in immune defense and enhancing the body's ability to clear pathogens. However, in various disease states, the C5a-C5aR1 pathway primarily shapes the disease microenvironment through regulating cellular pro-inflammatory and immune functions, angiogenesis processes, and tissue repair processes. It also promotes tumor immune escape through a novel mechanism through modulating the polarization of myeloid-derived suppressor cells (MDSCs) and regulating T cell function. The C5a-mediated "inflammation-fibrosis-metabolic reprogramming" vicious cycle has become a key molecular basis driving disease progression, maintaining pathological states, and promoting abnormal tissue damage repair in chronic inflammatory diseases. Through elucidating the structural biology of C5aR1 and designing allosteric modulators, nanobodies, and bifunctional molecules as new targeted intervention strategies, we aim to accelerate research progress in related medical fields. This article reviewed the molecular mechanisms of the complement system in tumor immune escape, chronic inflammation, fibrosis, and cardiovascular diseases, and explored the translational potential of targeted interventions. These discussions provide a solid theoretical foundation and new research perspectives for the medical field, aiding in the advancement of further discoveries.