# Neuro-Oncological Perspectives on Cancer Stem Cell Biology in Glioblastoma: Implications for Resection, Recurrence, Targeted Therapy, and Other CNS Tumors

## TL;DR

This paper explores how cancer stem cells in glioblastoma contribute to tumor recurrence and resistance to treatment, suggesting new strategies for targeting these cells and their environment.

## Contribution

The paper highlights the role of interconnected niches in supporting CSCs and proposes multimodal therapies to target CSCs and their microenvironment.

## Key findings

- Cancer stem cells are found beyond contrast-enhancing tumor margins, explaining tumor recurrence.
- CSCs are supported by multiple niches that promote therapy resistance and phenotypic plasticity.
- Multimodal therapies targeting both CSCs and their niches are needed for sustained treatment response.

## Abstract

What are the main findings?
Interconnected niches support cancer stem cells (CSCs) by promoting phenotypic plasticity and multi-mechanism therapy resistance.CSCs are found in the infiltrative zone beyond contrast-enhancing tumor margins.

Interconnected niches support cancer stem cells (CSCs) by promoting phenotypic plasticity and multi-mechanism therapy resistance.

CSCs are found in the infiltrative zone beyond contrast-enhancing tumor margins.

What are the implications of the main findings?
Longitudinal therapeutic outcomes are increasingly dictated by the success or failure of total CSC eradication.Sustained therapeutic response will likely require multimodal approaches.

Longitudinal therapeutic outcomes are increasingly dictated by the success or failure of total CSC eradication.

Sustained therapeutic response will likely require multimodal approaches.

Cancer stem cells (CSCs) are increasingly recognized as central drivers of tumorigenesis, therapeutic resistance, and recurrence across diverse malignancies. This review synthesizes our current understanding of CSC biology across CNS tumors, with a focus on glioblastoma, where stem-like cells are sustained by specialized and overlapping tumor microenvironmental niches. Perivascular, hypoxic, invasive, immunosuppressive, and extracellular matrix-associated niches cooperatively enforce stemness, metabolic adaptability, immune evasion, and phenotypic plasticity, enabling CSC persistence despite maximal surgical resection and standard-of-care therapy. Notably, CSCs extend beyond radiographically defined tumor margins and populate peritumoral regions, providing a biological basis for near-universal recurrence. Advances in multiparametric imaging, stem cell-based ex vivo and in vivo models, and single-cell and spatial profiling have refined insight into CSC heterogeneity, niche dependence, and treatment resistance. Together, these findings reframe therapeutic strategies, highlighting the need for function-preserving maximal resection and multimodal therapies that target both CSC-intrinsic pathways and their supportive microenvironments.