Glioma-Immune crosstalk in the tumor microenvironment: mechanistic insights and therapeutic translation.

Tumor progression is governed not only by genetic alterations but also by the dynamic interplay within the tumor microenvironment (TME). In gliomas, this microenvironment is shaped by diverse immune populations, including regulatory T cells and tumor-associated macrophages (TAMs), which influence tumor growth through direct interactions and cytokine signaling. A central challenge in glioma therapy is predicting patient response to immunotherapy, as both glioma cells and the TME evolve from diagnosis to recurrence. Advances in spatial transcriptomics and proteomics reveal that gliomas are composed of distinct molecular regions with unique lineage markers and biological behaviors. This heterogeneity underscores the limitations of single biopsies and highlights the need for multi-regional and longitudinal sampling. Serial biopsies and resections are therefore essential to capture tumor evolution and guide personalized immunotherapy. Standard glioblastoma (GBM) treatments, including radiation and temozolomide, also reshape immune cell dynamics, yet their contributions to therapy resistance remain incompletely understood. Clarifying these effects may inform more effective combination strategies. While TAMs dominate current research due to their prevalence in the glioma milieu, expanding focus to other immune cell subsets is critical for a more complete understanding of tumor-immune interactions. This review explores how radiotherapy, chemotherapy, and emerging immunotherapies reprogram the glioma TME by altering immune cell infiltration, cytokine networks, and stromal interactions. A deeper understanding of these processes will be vital for developing personalized and durable therapeutic approaches for glioma patients.