Precancer-Associated Microglia Restrain Glioblastoma Evolution Through Phagocytic Clearance

초록

Glioblastoma (GBM) is the most aggressive primary brain malignancy in adults, yet predominant late-stage diagnosis has hindered comprehensive understanding of the precancer stage of GBM. In particular, the tumor microenvironment (TME)—a crucial component of GBM biology—and how it co-evolves with emerging GBM during the precancer stage remain poorly understood. To address this gap, we applied scRNA-seq in a spontaneous GBM mouse model to longitudinally track mutant and microenvironmental cell populations throughout the evolutionary trajectory from precancer to cancer stages. We identified a cellular transition from oligodendrocyte progenitor (OPC)-like cells to mesenchymal (MES)-like cells as a principal event associated with precancer-to-cancer evolution. Notably, we discovered a previously unrecognized microglial population, termed Precancer-Associated Microglia (PAM), displaying enhanced phagocytic activity that distinguished them from tumor-associated microglia/macrophages (TAM). PAM depletion significantly accelerated GBM growth, underscoring the tumor-suppressive role of PAM during GBM evolution. Moreover, PAM preferentially engulfed MES-like cells while sparing OPC-like cells and their normally differentiated progeny, markedly constraining intratumoral heterogeneity—a defining hallmark of advanced GBM. These observations were validated in human scRNA-seq datasets from subventricular zone (SVZ)-tumor paired samples, revealing human PAM populations with pronounced phagocytic features distinct from TAM. Together, these findings establish PAM as a critical intrinsic host defense mechanism against early brain tumorigenesis through selective phagocytic elimination.