Complement-Targeted Therapies in Glioblastoma: A Systematic Review

Background/Objectives: Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults, with a median survival of approximately 15 months despite maximal multimodal therapy. The complement system plays a paradoxical dual role in GBM, mediating both antitumor immunity and immunosuppressive signaling within the tumor microenvironment, yet no systematic synthesis of complement-targeted therapeutic strategies exists. We aimed to comprehensively identify, appraise, and synthesize studies investigating complement-targeted therapies and complement-associated prognosis in GBM. Methods: Following PRISMA 2020 guidelines, we searched PubMed/MEDLINE and the Cochrane Library (CENTRAL) without date or language restrictions. Preclinical and clinical study designs were eligible. Risk of bias was assessed using SYRCLE, ROBINS-I, and study-type-specific checklists. Certainty of evidence was evaluated using GRADE. Statistical pooling was planned only for sufficiently comparable studies; clinical prognostic studies were synthesized narratively because they assessed non-equivalent constructs. Results: Forty-one studies were included, comprising 15 preclinical in vivo, 13 preclinical in vitro, 6 clinical observational, and 7 bioinformatics studies. Five preclinical survival studies entered a structured quantitative synthesis, but no pooled cross-target effect was calculated because their interventions, comparators, and reported summary measures were non-equivalent. Clinical prognostic studies evaluated either individual protein biomarkers or multigene immune-risk signatures and were not pooled. GRADE certainty was "Very Low" for both outcomes. C3b opsonization and the C5a/C5aR1 axis were among the most frequently studied targets. Conclusions: Complement modulation remains a promising biological hypothesis in GBM rather than evidence for clinical application, and certainty of evidence is very low. Methodological and mechanistic heterogeneity across complement targets underscore the need for standardized preclinical models and randomized clinical trials.