Fig. 1

Glioma local microenvironment and main associated changes. The glioblastoma (GBM) has highly immunosuppressive tumor microenvironment (TME) consisting of considerable cells, cytokines, chemokines and microvessels. TGF-β will transfer the fibroblast into cancer-associated fibroblast (CAF); there will be more epithelial mesenchymal transition (EMT) under IL-1β, IL-6 and TNF-α; with VEGF, there will be more abnormal vessel growth. With IL-10, TGF-β, M-CSF and IL-35, M2-macrophage polarization will be enhanced and regulatory T cells (Tregs) will inhibit immune activity of CD8 + T cells by secreting IL-10, TGF-β, M-CSF and IL-35. The tumor cells highly express immune suppressive factors like programmed cell death ligand 1 (PD-L1), IDO and decreases the level of MHC to inhibit tumor antigen recognition and presentation. In GBM TME, the microglial cells always downregulate potential immune response and promotes systematic immunosuppression by secreting TGF-β and IL-10. Tumor-associated macrophages (TAMs) has two subtypes, namely immunopromoting subtype (M1) and immunosuppressive subtype (M2). TAMs mediate and balance tumor immune activity by highly expressing PD-L1 and secreting TGF-β, IDO, CXCR4, IL-10, CXCL12, CCL20, CCL22 etc. MDSCs highly secrete IL-10, IL-12, TGF-β, TNF-α, IDO to inhibit immunotherapy response. Immature DCs can secrete some factors and express PD-L1, however, role of immature dendritic cells (DCs) is not determined. Tregs mediate immunosuppressive effects through upregulation of various soluble factors, immune checkpoints and metabolic pathways. Due to the increased levels of checkpoint exhaustion molecules, exhausted T cells downregulates immune response. Neutrophil and natural killer cells (NK cells) participates in the regulation of immunotherapy by upregulating G-CSF, S100A4 and IFN-γ, while clear role of B cell in GBM TME is not well established. Extracellular matrix (ECM) also serves as an important component in GBM TME. Vascularization is observed to be reinforced in GBM immunosuppressive TME, therefore anti-vascularization can be useful target to treat GBM. Immune cells, for example DCs, can migrate via tumor draining lymph nodes of the brain to deep cervical lymph nodes and promote tumor antigen to promote an adaptive antitumor immune response. The process can also be suppressed by the local immunosuppressed TME. On one hand, the bone marrow can restore and release suppressed T cells, on the other hand, chemotherapy (eg., TMZ) to GBM can induce lymphopenia that is exacerbated by bone marrow sequestration of T cells. Specific T cells to tumor antigens can be destroyed by spleen. Green arrow indicates the factors or activities are upregulated. CSF, colony stimulating factor; APC, antigen-presenting cells; IDO, indolamine 2,3-dioxygenase; MHC, major histocompatibility complex