###### Abstract  
Glioblastoma multiforme (GBM) represents the deadliest form of brain cancer, characterized by complex interactions within its microenvironment. Despite the understanding of GBM biology, GBM remains highly resistant to any therapy. Therefore, defining innovative biomarkers in GBM can provide insights into tumor biology and potential therapeutic targets. In this study, we explored the potential of GPRC5A to serve as a pertinent biomarker for GBM. We utilized the GBM-TCGA dataset and presented the reproducible bioinformatics analysis for our results. We identified that GPRC5A expression was significantly upregulated in GBM compared to normal tissues, with higher levels correlating with poor overall survival (OS) and progression-free interval (PFI). Moreover, it was associated with key genetic mutations, particularly _NF1_ and _PTEN_ mutations, and strongly correlated with the mesenchymal stem-like phenotype. GPRC5A was also predominantly associated with aggressive GBM features, including hypoxia, high extracellular matrix (ECM) environments, and extensive stromal and immune infiltrations. Its strong correlation with mesenchymal markers and hypoxic regions underscores its potential as a biomarker and therapeutic target in GBM. These findings provide valuable insights into the role of GPRC5A in GBM pathology and its potential impact as a target for GBM stratifications and treatment strategies. gioblastoma; tumor microenvironment; mesenchymal; immune cells; biomarkers; cancer stem cells +
Footnote †: journal: Medical  
metastasis, and resistance to apoptosis [2; 13; 14]. Therefore, understanding the molecular and cellular mechanisms driving these interactions is essential for developing effective therapeutic strategies. The GBM landscape not only varies among patients but also among different regions of the same tumor. These discrepancies are driven by factors such as clonal evolution, selective pressure from the TME, and molecular changes induced by therapy. As a result, biomarkers that may be indicative of disease in one patient or tumor region might not be applicable to others, complicating the development of universally applicable diagnostic and therapeutic targets [15]. Although the current genetic biomarkers offer some clinical insight, their predictive value is often limited and inconsistent across patients due to the high degree of GBM molecular and cellular heterogeneity [16]. Intratumoral heterogeneity is further amplified by the presence of rare, highly specialized clones known as cancer stem cells (CSCs) in tumor bulk, characterized by their ability to self-renew and differentiate into various cell types within the tumor [7; 17]. Even after aggressive treatment and apparent tumor clearance, CSCs can persist and drive tumor relapse and recurrence [18]. This resilience is primarily attributed to their intrinsic plasticity and ability to adapt to environmental changes, driven by dynamic epigenetic modifications and transcriptional reprogramming [19]. These clones are identified through several marker types, such as transcription factors, signaling kinases, epigenetic factors, metabolic modulators, and surface markers. However, these markers can be found across several solid cancers and in normal stem cells, limiting the specificity to properly targeting the GBM-CSCs [20; 21]. Despite advancements in understanding CSCs, there remains no consensus on their phenotypic characterization, spatial distribution within tumors, or the diverse sub-clones that can persist and contribute to tumor heterogeneity. Additionally, traditional diagnostic approaches, such as imaging and histopathological analysis, have limitations in capturing CSCs and the intricate molecular landscape of GBM, resulting in suboptimal treatment strategies for tumor progression [22]. Therefore, there is an urgent need for novel biomarker discovery, along with a comprehensive molecular investigation to better understand CSCs and TME complexity and improve clinical outcomes.