Mechanisms of cancer stem cell senescence: Current understanding and future perspectives

Abstract Cancer stem cells (CSCs) are a small population of heterogeneous tumor cells with the capacity of self‐renewal and aberrant differentiation for immortality and divergent lineages of cancer cells. In contrast to bulky tumor cells, CSCs remain less differentiated and resistant to therapy even when targeted with tissue‐specific antigenic markers. This makes CSCs responsible for not only tumor initiation, development, but also tumor recurrence. Emerging evidence suggests that CSCs can undergo cell senescence, a non‐proliferative state of cells in response to stress. While cell senescence attenuates tumor cell proliferation, it is commonly regarded as a tumor suppressive mechanism. However, mounting research indicates that CSC senescence also provides these cells with the capacity to evade cytotoxic effects from cancer therapy, exacerbating cancer relapse and metastasis. Recent studies demonstrate that senescence drives reprogramming of cancer cell toward stemness and promotes CSC generation. In this review, we highlight the origin, heterogeneity and senescence regulatory mechanisms of CSCs, the complex relationship between CSC senescence and tumor therapy, and the recent beneficial effects of senotherapy on eliminating senescent tumor cells.