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Introduction
Gliomas, which account for over 80% of malignant brain tumors, are the most prevalent primary CNS tumors, with prominent recurrence propensity posing significant clinical challenges [1]. According to the World Health Organization (WHO) classification, the majority of gliomas are diffuse and stratified into three molecular subtypes: (1) Isocitrate dehydrogenase (IDH) mutant-1p/19q co-deleted (oligodendroglioma), (2) IDH-mutant-1p/19q retained (astrocytoma), and (3) IDH-wildtype glioblastoma (GBM) [2]. Although significant progress has been made in therapeutic modalities including surgical resection, radiation therapy, and systemic chemotherapy, the median overall survival period of patients with GBM remains less than 16 months [3]. In recent years, immunotherapy has come to the fore as a potentially effective treatment method for patients suffering from malignant tumors, including glioma [4, 5]. However, only a subset of glioma patients responds to immunotherapy. GBM, the most aggressive subtype, demonstrates extreme invasiveness and poor prognosis, with a mere 5.6% 5-year survival rate post-diagnosis [2, 6].
The 26S proteasome consists of the 20S proteasome, 19S (PA700) and 11S (PA28) [7]. The 20S proteasome represents the catalytic core of this enzymatic system, comprising two α-rings and two β-rings (α₁₋₇β₁₋₇β₁₋₇α₁₋₇), with each ring comprising seven subunits. The external α-rings play a critical role in controlling substrate entry into the internal catalytic domain, which is constituted by β-subunits [8]. When the PA700 and PA28 regulatory complexes associate with the α-rings of the core particle, they give rise to the 26S proteasome and immunoproteasome, respectively. Notably, the 20S proteasome is recognized for its ability to degrade oxidized proteins, a process that operates independently of ubiquitination [7]. The proteasome mediates the degradation of ubiquitinated proteins, enabling rapid intracellular turnover and generating the primary source of peptide antigens for major histocompatibility complex class I (MHC-I) presentation [9]. Proteasome subunit beta type-8 (PSMB8/LMP7), a catalytic β subunit (β5i) of the 20S proteasome, is transcriptionally upregulated by interferon-gamma (IFN-γ) [10]. A recent analysis showed that high PSMB8 methylation is associated with an inhibitory response to immunotherapy [11]. A previous study demonstrated that PSMB8 optimized the antigen presentation of MHC-I-restricted epitopes to CD8+ T cells by cleaving proteins after their basic and hydrophobic residues [12]. Moreover, during the development of colitis-associated colonic cancer, the pro-tumoral capacity of immunoproteasomes appears to contribute to carcinogenesis by triggering the...