Colorectal cancer stem cells in the tumor microenvironmental niche: Mechanistic insights and emerging therapies.

Colorectal cancer (CRC) is a highly heterogenous disease, wherein a specific population of cancer stem cells (CSCs) are crucial in tumor initiation, therapeutic resistance, metastasis and disease progression. The tumor microenvironment (TME) plays a key role in the development of CRC stem cells (CCSCs) by sending signals and allowing cells to interact with each other, which helps to stem cells stay viable and regenerate. The ongoing interaction between CCSCs and diverse components of TME promotes treatment resistance and tumor recurrence. Recent advancements permitted the fabrication of three-dimensional (3D) tumor models using CCSCs. These models better replicate the in vivo TME and provide useful ways in personalized drug discovery and tumor biology. Therapy resistance in CCSCs is still an important concern in CRC therapy, because cells remain active, have good DNA repair systems, and interact with other cells in the TME. Targeted treatment techniques are being formulated to interrupt in various pathways, including DNA/RNA-based methods that inhibit oncogenic drivers or restore tumor suppressors in CCSCs. TME-targeted immunotherapies, including immune checkpoint inhibitors, T-cell-based treatments, and cytokine modulation, are shown potential in counteracting immune evasion by CCSCs. Numerous clinical trials are examining the effectiveness of inhibitors targeting CCSC-related pathways in metastatic CRC. This review comprehensively explores the evolution and role of CCSC within the TME, development of 3D TME models from patient derived stem cells, mechanism of resistance and targeted immunotherapeutic strategies aimed at eradicating CSCSs to improve clinical outcomes in CRC.