Glioblastoma is the most aggressive form of brain tumor resulting in low overall patient survival rates of 12–15 months post diagnosis. Several factors contribute to the complexity of the tumor, including tumor heterogeneity, blood–brain barrier complications, genetic defects, cancer stem cell generation, and immune evasion. These factors can result in the progression of glioblastoma and are controlled by signaling pathways. Some of the signaling pathways involved in glioblastoma progression include ERK, NF-κB, Wnt, and PI3K/AKT/mTOR. Our and others’ previous studies have found that TIM-3 and TGF-β signaling is altered in glioblastoma patients and may contribute to cancer progression. Immune promoting pathways such as STING have also been studied in glioblastoma to enhance anti-tumor immunity; however the interconnecting roles of these pathways are not well described. This review highlights the role of these three key cancer-related pathways in glioblastoma and their mechanistic link. Better understanding these links may result in improved treatment targets or disease progression biomarkers.