Reshaping the immunosuppressive glioma microenvironment: mechanisms, biomarkers, and emerging immunotherapies

Gliomas encompass biologically distinct subtypes with different clinical behaviors and immune microenvironments. IDH-wildtype glioblastoma (GBM), the most aggressive subtype, has a median survival of 14-18 months, while IDH-mutant gliomas (including grade 2-4 astrocytomas and oligodendrogliomas) have significantly better prognoses (median OS 3-8 years; Cancer Genome Atlas, NEJM 2015). Throughout this review, we specify the glioma subtype when discussing each mechanism and therapeutic strategy. Although immunotherapy has achieved major breakthroughs in multiple solid tumors, its clinical efficacy in glioma remains consistently limited. Accumulating evidence indicates that a profoundly immunosuppressive tumor immune microenvironment is the principal barrier to successful immunotherapy in glioma. Therefore, systematically reshaping this immunosuppressive state has become a central research priority. This narrative review summarizes the establishment and regulatory mechanisms of the immunosuppressive microenvironment in glioma, outlining global immune characteristics and key cellular and molecular foundations. We focus on the myeloid-cell network dominated by tumor-associated macrophages (TAMs) and microglia, T-cell dysfunction, and the pivotal roles of immunosuppressive signaling pathways and metabolic reprogramming in sustaining immune suppression. In addition, we comprehensively review candidate biomarkers associated with immunotherapy response, including multidimensional indicators at molecular, cellular, and spatial levels, and emphasize their potential value for patient stratification and treatment decision-making. Building on this framework, we further analyze recent progress in emerging immunotherapeutic strategies for glioma-such as immune checkpoint inhibitors (ICIs), tumor vaccines, cellular immunotherapies, and oncolytic viruses-together with the major causes underlying their constrained efficacy. We reinterpret clinical outcomes through the lens of the immune microenvironment. By integrating available evidence, this review highlights the importance of combination regimens aimed at microenvironmental remodeling to overcome immune tolerance, and discusses key challenges and future directions. Overall, we propose that remodeling the immunosuppressive microenvironment-rather than merely enhancing immune activation-is a prerequisite for meaningful breakthroughs in glioma immunotherapy. A deeper understanding and more precise intervention of the immune microenvironment may yield clinically substantive benefits for patients with glioma.