Bridging MBD3 functions in developmental biology and glioma heterogeneity to immune remodeling with future perspectives.

Glioblastoma (GBM) remains one of the most lethal and treatment-refractory brain tumors, characterized by rapid recurrence and profound resistance to conventional therapies. The mechanisms underlying GBM resilience converge on two interdependent axes: intratumoral heterogeneity and adaptive tumor microenvironment (TME) remodeling, which engage in reciprocal crosstalk to promote immune evasion, invasion, and tumor persistence. Epigenetic regulation has emerged as a central determinant of tumor plasticity and cellular adaptability within this context. Methyl-CpG-binding domain protein 3 (MBD3), a core structural and regulatory component of the NuRD complex, represents a functionally distinctive epigenetic regulator that operates beyond canonical methylation-dependent pathways. With well-established roles in lineage commitment and neural development, MBD3 has been increasingly implicated in GBM progression, glioma stem cell maintenance, and therapeutic resistance. In parallel, GBM actively co-opts non-neoplastic TME components - including microglia, the resident innate immune sentinels of the central nervous system - which exert context-dependent tumor-supportive and tumor-suppressive functions. Understanding how MBD3 shapes tumor-immune interactions and modulates innate immune regulation is therefore of growing biological and translational importance. This review provides an overview of the MBD protein family and delineates the multifaceted roles of MBD3 in developmental and GBM biology, with particular emphasis on tumor-intrinsic heterogeneity and TME remodeling. By integrating epigenetic, cellular, and immunological perspectives, we highlight emerging evidence linking MBD3 to tumor plasticity and immune modulation, and propose hypothetical regulatory frameworks that warrant experimental investigation. Clarifying the context-dependent functions of MBD3 may yield mechanistic insights into GBM pathogenesis and inform the development of novel epigenetic therapeutic strategies.