Unveiling anaphylatoxins: Pioneering cancer therapies through complement system insights

Abstract

The complement system, a cornerstone of innate immunity, plays pivotal roles in both defense and pathology, particularly through its anaphylatoxins, C3a and C5a. These small peptides, generated during complement activation, not only mediate pro-inflammatory responses but also contribute to the progression of various cancers by modulating the tumor microenvironment (TME). Anaphylatoxins influence tumor cell proliferation, epithelial-mesenchymal transition, angiogenesis, immune suppression, and therapy resistance via key signaling pathways such as PI3K/AKT, MEK/ERK, and p38 MAPK. This review summarizes recent findings on the roles of C3a and C5a in different tumor types, including glioma, lung cancer, melanoma, breast cancer, and hematological malignancies, highlighting their potential as biomarkers and therapeutic targets. Additionally, we discuss the development of anaphylatoxin inhibitors, their clinical applications, and the synergistic effects of combining these inhibitors with immune checkpoint blockade therapies. A deeper understanding of anaphylatoxin-mediated mechanisms may provide novel strategies for cancer diagnosis, prognosis, and treatment, paving the way for targeted and combination therapies to overcome tumor progression and immune evasion.