Targeting cancer stem cells as the most aggressive and tumor-initiating cells

• Cancer stem cells (CSCs), as the most aggressive and tumor-initiating cells, play a fundamental role in driving key malignant behaviors in cancer. • CSCs exhibit low immunogenicity, enabling them to evade recognition and destruction by the immune system. CSCs also contribute to an immunosuppressive tumor microenvironment. • Conventional cancer therapies have significant limitations in effectively targeting CSCs. • Since CSCs are responsible for tumor repopulation after tumor cell destruction, targeted elimination of CSCs is critical for complete tumor eradication. • A combination of immunotherapy and cytotoxic treatments to eliminate CSCs and non-CSCs simultaneously will lead to complete eradication of cancer. Cancer stem cells (CSCs) are a small subpopulation of tumor cells characterized by their self-renewal capacity and the ability to differentiate into different cell types. These partially differentiated cells exhibit properties of both stem cells and cancer cells. CSCs drive tumor initiation and progression by generating additional stem cells through self-renewal and differentiation into heterogeneous populations of tumor cell. They are among the most aggressive tumor cells that contribute to the development of key features of malignancy such as increased proliferation, metastasis, tumor growth, multidrug resistance (MDR), and resistance to radiotherapy and chemotherapy. CSCs are also associated with relapse and minimal residual disease, highlighting their critical role in cancer persistence. Therefore, targeting CSCs is essential to achieve complete tumor eradication. Available evidence suggests that combination therapies that integrate immunotherapy with cytotoxic therapies to concurrently eliminate CSCs and non-CSCs offer a promising approach to completely eradicate cancer. This review summarizes the current strategies employed to target CSCs and improve cancer treatment outcomes.