Gliomas are the most common malignant primary brain tumors, arising from glial cells and displaying a wide spectrum of biological characteristics and clinical behaviors [1]. In Europe, their annual incidence is estimated at approximately 5.5 cases per 100,000 inhabitants [2]. By contrast, lower rates have been reported in Tunisia, with approximately 0.18 cases per 100,000 men and 0.09 cases per 100,000 women [3]. Although gliomas may occur at any age, their incidence increases sharply after the age of 40 and peaks around 65 years [1].

Despite extensive research, the pathogenesis of gliomas remains incompletely understood. Gliomagenesis involves a complex interplay of genetic alterations and dysregulated signaling pathways in proliferating neural cells, giving rise to marked phenotypic variability and intratumoral heterogeneity [4]. Among gliomas, glioblastoma is the most frequent and aggressive subtype, accounting for 60–70 % of cases. The prognosis remains poor, with a median survival of 12–18 months [2,5]. Nevertheless, a subset of patients demonstrates unexpectedly prolonged survival, highlighting the need to further explore molecular pathways that may explain this variability [4]. Among these, the DNA mismatch repair (MMR) system and microsatellite instability (MSI) have emerged as areas of particular interest [6].

The MMR system preserves genomic integrity by correcting base-base mismatches and insertion-deletion loops introduced during DNA replication [7]. It is regulated by several key genes, including mutL homolog 1 (MLH1) on chromosome 3p21.3, mutS homolog 2 (MSH2) on chromosome 2p22-21, mutS homolog 6 (MSH6) on chromosome 2p16, and post-meiotic segregation increased 2 (PMS2) on chromosome 7p22.2. The encoded proteins recognize and repair mismatched nucleotides, thereby preventing mutation accumulation [8,9]. Deficiency in the MMR system may result from germline or somatic mutations, or from promoter hypermethylation, leading to genomic instability, which is particularly evident within microsatellite sequences, short and repetitive DNA sequences prone to replication errors [6,10]. When such errors remain uncorrected, MSI ensues, a hypermutable phenotype characterized by an increased mutation burden [11].

MSI has been linked to tumorigenesis, poor prognosis, and resistance to alkylating agents, such as temozolomide, which induce O6-methylguanine mismatches [12]. Moreover, MSI is increasingly recognized as a predictive biomarker for immunotherapy, particularly immune checkpoint inhibition [6,11].

Given the key role of MMR in maintaining genomic stability and its association with MSI, evaluating MMR and/or MSI status in gliomas may provide valuable insights into tumor biology, prognosis, and therapeutic response [13]. A deeper understanding of these molecular mechanisms could contribute to the development of more personalized treatment strategies, thereby ultimately improving patient outcomes. In this study, we indirectly assessed the MSI profile of gliomas through MMR protein expression and investigated its clinicopathological and prognostic relevance in a cohort of Tunisian patients.