The Role of Complement Anaphylatoxins (C3a and C5a) in Non-small Cell Lung Cancer: A Systematic Review

The complement anaphylatoxins C3a and C5a are critical effectors of innate immunity. Beyond this role, emerging evidence has implicated them in cancer progression. However, their specific functions in non-small cell lung cancer (NSCLC) have not been systematically reviewed. This review aimed to synthesize the evidence on the contribution of C3a and C5a to NSCLC progression and their potential as therapeutic targets. This systematic review followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive search of PubMed, Scopus, and Cochrane Library was performed up to May 2025. The PICO (Population, Intervention, Comparison, Outcome) framework guided the inclusion of studies involving NSCLC patients or human cell lines, reporting on C3a/C5a levels and their association with clinical outcomes or pro-tumoral effects. The risk of bias was assessed using the OHAT tool. From 11,838 initially identified records, six studies met the inclusion criteria based on PICO criteria requiring direct investigation of C3a/C5a in human NSCLC contexts. The evidence strongly and consistently points to a critical pro-tumoral role for the C5a/C5aR1 axis. Key findings include: C5a promotes NSCLC cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition; high C5aR1 expression is an independent prognostic factor for worse recurrence-free survival; and tumor-derived C5a enhances angiogenesis and metastatic potential, particularly to bone. NSCLC cells evade complement attack by producing regulators like Factor H. In contrast, the role of C3a was less defined. While C5a was consistently elevated and active in the tumor microenvironment, one study noted a local decrease of C3a in tumor tissues, suggesting a potentially different or context-dependent function. Risk of bias assessment using the OHAT tool indicated low to moderate risk across the included studies. This systematic review shows that complement anaphylatoxins, especially C5a, drive NSCLC progression by promoting a pro-tumoral microenvironment and metastasis. Targeting the C5a/C5aR1 axis is a promising therapeutic strategy, though more research is needed.