Targeting the C3 signaling axis of the complement system: immune microenvironment regulation and emerging therapeutic strategies for glioblastoma

Glioblastoma (GBM) is the most malignant primary brain tumor, with treatment resistance tightly linked to the intricate regulation of the tumor immune microenvironment (TME). In recent years, the complement system-especially its central component C3 and its cleavage products C3a/C3aR signaling-has drawn increasing attention for its roles in GBM initiation and progression. This review systematically delineates the expression patterns of C3 in GBM, its regulatory mechanisms, and its connections to key biological processes such as hypoxia, immunosuppression, and angiogenesis. We provide a comprehensive analysis of the potential of targeting C3/C3aR signaling as a novel GBM therapy, including the application of small-molecule antagonists, synergistic effects with radiotherapy, and the prospects for biomarker development based on liquid biopsy. All therapeutic claims are based predominantly on preclinical evidence; clinical translation remains to be validated. By integrating the latest findings, this work aims to offer new perspectives and theoretical support for understanding GBM immune evasion and for the development of precise immunotherapies.