A possible immune shield
Complement regulators may give glioma cells an active defense against immune surveillance. A systematic review reports that glioma cells synthesize, secrete and epigenetically regulate complement inhibitors in a pattern described as helping them evade immune surveillance. It also links specific regulators with proliferation, invasion and treatment resistance. The review is a map of mechanisms reported across different kinds of research, not evidence that targeting these proteins improves care for patients.
The review followed PRISMA 2020, a reporting framework for systematic reviews, and searched PubMed, Scopus, Embase and Web of Science through November 2025. Eligible work included in vitro, in vivo and clinical investigations of complement regulators in glioma. Twenty-one experimental studies met the inclusion criteria. The review does not report how many studies fell into each design.
How the proteins may blunt immune attack
One group of findings concerned soluble regulators, proteins that can operate outside the cell. CFH, FHL-1 and FHR5 were linked to binding on the tumor-cell surface, accelerated convertase decay and protection from complement-mediated cytolysis, the cell-killing action examined in these studies. These results describe a possible route to tumor-cell protection, but no numerical effect estimate was reported.
CFH was also described as a novel ICOS ligand on regulatory T cells. In that setting, PI3K/Akt activation was linked to enhanced immunosuppression. The review therefore places CFH in a pathway associated with dampening immune activity, not only in the machinery that protects a tumor cell from complement-mediated damage.
Another strand involved circ-CFH and miR-149. The review links circ-CFH, miR-149 sponging and AKT1-associated proliferation. Here, sponging means one molecule is described as binding up a small RNA, a shorthand for the molecular relationship reported in the studies. The finding is a mechanistic association, so it does not show that the pathway determines how an individual patient's tumor will behave.
Links to invasion and treatment resistance
Factor I points to a different possible role. It was reported as upregulated in high-grade gliomas and linked to tumor invasion through VEGF-FAK signaling. The finding extends the review's focus beyond immune suppression, although it reports no pooled measure of the association.
Clusterin featured in two strands of the evidence. In one, clusterin was transferred from extracellular vesicles produced by glioblastoma stem cells to macrophages. Those studies reported the transfer alongside M2 polarization, a shift in macrophage state, and resistance to temozolomide. The review reports the events together; it does not establish from this evidence alone that clusterin transfer caused the resistance.
In another line of work, clusterin silencing was associated with glioma-cell sensitivity to senolytic therapy, treatment designed to target senescent cells, as well as with oxidative stress and apoptosis, a form of programmed cell death. That result adds a possible connection between clusterin and treatment response, but it remains a study-level association in the review.
What the review can and cannot answer
Among membrane-bound regulators, CD59 was identified as the dominant inhibitor of the terminal lytic complex, the final cell-damaging stage described in the complement pathway. It was considered more functionally important than CD46. That ranking may help set priorities for future investigation, but it is not a clinical comparison showing that one treatment is better than another.
The authors' broader interpretation is that complement regulators may extend beyond passive immune evasion toward tumorigenesis and therapeutic resistance. They propose the proteins as prognostic biomarkers, markers intended to help predict outcomes, and as therapeutic targets. The evidence summarized does not validate those biomarkers or show that targeting them improves survival or treatment response in humans.
The synthesis was qualitative. The supplied analysis reports no pooled effect estimates, confidence intervals, P values or quantitative heterogeneity measures, and it does not provide a common review-level comparator. The study counts and findings are also not separated by in vitro, in vivo and clinical design. Those gaps leave open whether the mechanisms translate into better outcomes or which complement-regulator interventions could be combined effectively with immune or chemotherapy.
The article reports no specific grants from public, commercial or not-for-profit funding agencies, and its authors declare no conflicts of interest. The datasets generated or analyzed in the study are stated to be available from the corresponding author on reasonable request.
Paper data and sources
Original title: Systemic and local dysregulation of the complement system in glioma: a comprehensive systematic review.
Authors: Omar Alomari, Tasneem Alomari, Beyzanur Güney et al.
Journal/Repository: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico
Status: Peer-reviewed
First online: 2026-08-21
DOI: 10.1007/s12094-026-04552-w
Original paper · Full text