Targeting colorectal cancer stem-like cells: Overcoming therapeutic resistance and reprogramming the...

Colorectal cancer stem-like cells (CRC-SCs) represent a tumor subpopulation with enhanced tumor-initiating capacity and have been implicated in metastasis, therapeutic resistance, and disease relapse. These cells not only possess intrinsic resistance mechanisms, such as quiescence, enhanced DNA repair, and ABC transporter overexpression, but also actively orchestrate a profoundly immunosuppressive tumor microenvironment (TME). Emerging evidence suggests that CRC-SCs may contribute to shaping an immunosuppressive TME through secretion of exosomes and cytokines that influence immune cells (e.g., regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages) and key stromal cell populations (e.g., cancer-associated fibroblasts). This review provides a comprehensive analysis of the evolving landscape of immunotherapies designed to target CRC-SCs. We evaluate immunotherapeutic strategies including immune checkpoint inhibitors, while also discussing the targeting of critical signaling pathways like Wnt, Notch, and Hh. Furthermore, we explore the growing role of artificial intelligence (AI)-based approaches in deciphering CRC-SC heterogeneity, identifying predictive biomarkers, and accelerating therapeutic target discovery. Despite these advancements, significant challenges remain, including tumor heterogeneity, the immunosuppressive TME, and on-target/off-tumor toxicity. We conclude by outlining future directions that emphasize combination therapies, novel delivery systems, and AI-driven precision medicine as crucial strategies to more effectively target CRC-SC populations and improve durable disease control.