Figure 2.

The cellular organization of immunologically “cold” and “hot” gliomas

Combined cytotoxic and immune-stimulatory gene therapy remodel the immunosuppressive TME to an inflamed hot glioma microenvironment. The GBM cold immunosuppressive TME is characterized by low infiltration of CD8⁺ T cells, DCs, and NK cells but high infiltration of immunosuppressive MDSCs, M2-polarized macrophages, and Tregs. The cold TME also has low expression and presentation of tumor antigens, which hinders the success of immunotherapy. However, combined cytotoxic and immune-stimulatory gene therapy remodels the TME to an immunostimulatory hot TME that attracts effector CD8⁺ T cells, DCs, NK cells, and fewer Tregs and MDSCs. Glioma-specific antigens and DAMPs released from dying glioma cells trigger immunogenicity and adjuvanticity, respectively. Ad-Flt3L injections promote the recruitment, infiltration, and activation of DCs, thereby enhancing antigen presentation, priming, and clonal expansion of glioma-specific CD8⁺ cytotoxic effector T cells. The figure was created with BioRender.com.