Cancer stem cell plasticity drives therapy resistance in colorectal cancer

Figure 3 Therapeutic strategies targeting colorectal cancer stem cells. Conventional therapies primarily eliminate rapidly proliferating non-cancer stem cells (CSCs) but frequently fail to eradicate therapy-resistant CSCs, resulting in tumor relapse and metastatic progression. Emerging combination strategies aim to overcome CSC-mediated resistance by simultaneously targeting CSC-associated signaling pathways, epigenetic regulators, tumor microenvironment components, immune checkpoints, and exosome-mediated communication. These multimodal therapeutic approaches are expected to inhibit CSC plasticity, prevent dedifferentiation, improve treatment response, and achieve durable clinical outcomes. In the final panel, eliminated/apoptotic CSCs represent treatment-induced cancer stem cell death, whereas the remaining differentiated cells represent tumor cells that have lost stem-like properties and entered a more treatment-sensitive state. The reduction in CSCs and residual tumor cells illustrates the intended durable therapeutic response. Symbols and colors are defined within the figure. CSC: Cancer stem cell; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; HDAC: Histone deacetylase; CAF: Cancer-associated fibroblast; ECM: Extracellular matrix; CAR-T: Chimeric antigen receptor T; siRNA: Small interfering RNA; miRNA: MicroRNA.