# Malignant Cells Beyond the Tumor Core: The Non‐Negligible Factor to Overcome the Refractory of Glioblastoma

## TL;DR

Glioblastoma recurrence is driven by malignant cells beyond the tumor core, which are highly invasive and resistant to treatment, requiring new strategies for better outcomes.

## Contribution

Highlights the critical role of Q cells beyond the tumor core in glioblastoma recurrence and their unique biological and physical properties.

## Key findings

- Q cells exhibit enhanced invasiveness, metabolic adaptations, and drug resistance.
- Advanced imaging techniques like DTI, MRS, and PET can detect Q cells for more precise surgical resection.
- Q cells reside in a distinct microenvironment influenced by physical properties like solid stress and stiffness.

## Abstract

Glioblastoma (GBM) is one of the most aggressive primary brain tumors in adults. Over 95% of GBM patients experience recurrence in the peritumoral brain tissue or distant regions, indicating the presence of critical factors in these areas that drive tumor recurrence. Current clinical treatments primarily focus on tumor cells from the tumor core (TC), while the role of neoplastic cells beyond the TC has been largely neglected.

We conducted a comprehensive review of existing literature and studies on GBM, focusing on the identification and characterization of questionable cells (Q cells). Advanced imaging techniques, such as diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET), were utilized to identify Q cells beyond the tumor core. We also analyzed the functional properties, cellular microenvironment, and physical characteristics of Q cells, as well as their implications for surgical resection.

Our review revealed that Q cells exhibit unique functional attributes, including enhanced invasiveness, metabolic adaptations, and resistance mechanisms. These cells reside in a distinct cellular microenvironment and are influenced by physical properties such as solid stress and stiffness. Advanced imaging techniques have improved the identification of Q cells, enabling more precise surgical resection. Targeting Q cells in therapeutic strategies could significantly reduce the risk of GBM recurrence.

The presence of Q cells in the peritumoral brain zone (PBZ) and beyond is a critical factor in GBM recurrence. Current treatments, which primarily target tumor cells in the TC, are insufficient to prevent recurrence due to the neglect of Q cells. Future research should focus on understanding the mechanisms influencing Q cells and developing targeted therapies to improve patient outcomes.

Located beyond the tumor core, questiona cells (Q cells) exhibit high invasiveness, metabolic adaptations, and drug resistance, driving tumor recurrence despite aggressive treatment. Their physical properties, such as low solid stress and soft tissue stiffness, further enhance their migratory and invasive capabilities. Advanced imaging techniques (e.g., DTI, MRS, DWI, PET) enable their detection, while interactions with the tumor microenvironment (e.g., TAMs, Tregs, fibroblasts) present new therapeutic challenges and opportunities.