Glioblastoma multiforme (GBM), the most aggressive primary brain malignancy, continues to pose an insurmountable therapeutic challenge due to its profound intratumoral heterogeneity, inherent drug resistance, and highly immunosuppressive tumor microenvironment [1]. The urgent need to identify actionable molecular targets to overcome these barriers has driven intensive research in GBM immunology and precision oncology. As core regulators of chromatin dynamics, inflammation, and immune modulation, the high mobility group (HMG) family is well-studied in cancer. Within it, HMGB1 and HMGB2 have been extensively investigated in GBM: HMGB1 drives GBM’s immunosuppressive TME via TLR4/Akt signaling, while HMGB2 correlates with GBM stem cell maintenance and radioresistance [2–4]. In contrast, the undercharacterized HMGB3 has only recently emerged as a potential onco-immunological target. Studies in non-small cell lung cancer (NSCLC) and breast cancer show HMGB3 overexpression links to tumor immune evasion and poor prognosis [5]. Against this backdrop, Wang et al.’s study, titled “Comprehensive bioinformatics analysis identified HMGB3 as a promising immunotherapy target for glioblastoma multiforme,” published in Discover Oncology, represents a significant step forward [6]. By leveraging multi-omics data and robust bioinformatics tools, the study systematically characterizes the role of HMGB3 in GBM pathogenesis, immunosuppression, and therapeutic responsiveness. This commentary evaluates the study’s core strengths, critically examines its limitations, and proposes targeted future directions to fully realize the translational potential of HMGB3 in GBM treatment. All analyses are strictly based on the content of the referenced manuscript throughout the study.

Bulk RNA-seq, Glioblastoma multiforme, HMGB3, scRNA-seq, Tumor microenvironment