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Abstract The immune system is an interacting network of plentiful molecules that could better characterize the relationship between immunity and cancer. This study aims to investigate the behavioral patterns of immune‐related interaction perturbation networks in glioblastoma. An immune‐related interaction‐perturbation framework was introduced to characterize four heterogeneous subtypes using RNA‐seq data of TCGA/CGGA glioblastoma tissues and GTEx normal brain tissues. The stability and robustness of the four subtypes were validated in public datasets and our in‐house cohort. In the four subtypes, C1 was an inflammatory subtype with high immune infiltration, low tumor purity, and potential response to immunotherapy; C2, an invasive subtype, was featured with dismal prognosis, telomerase reverse transcriptase promoter mutations, moderate levels of immunity, and stromal constituents, as well as sensitivity to receptor tyrosine kinase signaling inhibitors; C3 was a proliferative subtype with high tumor purity, immune‐desert microenvironment, sensitivity to phosphatidylinositol 3′‐kinase signaling inhibitor and DNA replication inhibitors, and potential resistance to immunotherapy; C4, a synaptogenesis subtype with the best prognosis, exhibited high synaptogenesis‐related gene expression, prevalent isocitrate dehydrogenase mutations, and potential sensitivity to radiotherapy and chemotherapy. Overall, this study provided an attractive platform from the perspective of immune‐related interaction perturbation networks, which might advance the tailored management of glioblastoma.