Complement receptor C3aR marks heterogeneous tumor‐associated macrophage states associated with improved survival in IDH‐wildtype glioblastoma

Abstract

Abstract Glioblastomas (GBM), IDH‐wildtype, are highly aggressive brain tumors with poor prognosis and inter‐individual variability despite established prognostic factors such as age, performance status, and MGMT promoter (MGMTp) methylation. Increasing evidence highlights the role of the tumor microenvironment (TME) in GBM progression. The complement system, a key component of innate immunity, can influence tumor growth and immune regulation through the generation of the anaphylatoxin C3a and the activation of its receptor, C3aR. While C3a/C3aR signaling has been associated with various outcomes in several malignancies, its prognostic relevance in GBM remains poorly defined. This study investigated the expression of C3aR in human IDH‐wildtype GBM and its association with clinicopathological features and overall survival. We retrospectively analyzed a cohort of 114 patients with IDH‐wildtype GBM. C3aR expression was assessed by immunohistochemistry and quantified using digital image analysis. C3aR expression was analyzed as a categorical variable using an outcome‐derived cutpoint (C3aR‐high and C3aR‐low) for exploratory purposes. Associations with clinical variables, including MGMTp methylation status, were evaluated. C3aR expression showed marked inter‐tumoral heterogeneity and was enriched among MGMTp‐methylated tumors (p = 0.004). Patients with C3aR‐high tumors exhibited improved overall survival (log‐rank p = 0.033). In a multivariable Cox regression model including age, performance status, surgery type, and MGMTp methylation status, high C3aR expression remained independently associated with improved overall survival (HR 0.50, 95% CI 0.29–0.87, p = 0.014). Tissue‐based and single‐cell analyses supported the association of C3aR with the myeloid/macrophage compartment and heterogeneous macrophage phenotypes. These findings support a relationship between C3aR expression and the heterogeneous macrophage landscape of IDH‐wildtype GBM, while the survival association remains exploratory and requires independent validation.