ABSTRACT: Glioblastoma (GBM) is the most lethal primary intracranial malignancy, characterized by aggressive recurrence and a dismal prognosis. Despite the implementation of multimodal standard-of-care therapies, including maximal surgical resection, radiotherapy, and chemotherapy, clinical outcomes remain unsatisfactory. A critical determinant of therapeutic resistance is the highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), which constitute 30-50% of the tumor mass, are the predominant immune population within the TME and key orchestrators of GBM-associated immunosuppression. While TAMs predominantly acquire a protumoral M2-like phenotype to facilitate tumor progression via the secretion of cytokines, angiogenic factors, and matrix metalloproteinases, the molecular mechanisms governing this polarization remain elusive. Herein, we identify the immunoregulatory receptor CD300A as a critical driver of M2 macrophage polarization in GBM. Analysis of clinical specimens demonstrated that CD300A is significantly upregulated in GBM tissues and positively correlates with the M2 marker CD163. In a macrophage model, we found that upon M2 induction, CD300A expression was markedly upregulated, paralleling the induction of canonical M2 markers, including CD206 and Arg-1. Functionally, ectopic overexpression of CD300A markedly upregulated canonical M2 markers CD206, Arg-1, and FIZZ1, whereas CD300A knockdown attenuated this phenotype. Mechanistically, we demonstrate that CD300A promotes M2 polarization by activating the JAK2/STAT3 signaling axis. Furthermore, CD300A-mediated M2 polarization was found to enhance the proliferation, migration, and invasion of GBM cells via the induction of VEGFA secretion. Collectively, our findings delineate a novel CD300A-JAK2/STAT3-VEGFA signaling axis that couples immune modulation with malignant progression, highlighting CD300A as a potential therapeutic target for modulating TAMs in GBM.
