Targeting asymmetric division in cancer stem cells: implications for relapse and resistance

Cancer stem cells (CSCs) represent a resilient subpopulation within tumors, capable of driving progression, metastasis, and recurrence. One mechanism that enables this plasticity is asymmetric cell division (ACD), a process by which CSCs generate both a self-renewing stem cell and a differentiated daughter cell. While traditionally associated with tissue development, ACD is now recognized as a dynamic and regulated feature of cancer biology, particularly in response to stress conditions such as hypoxia and radiation. In this review, we provide a comprehensive and mechanistic synthesis of how intrinsic factors such as polarity complexes, cell fate determinants (CFDs), spindle orientation cooperate with extrinsic cues from the tumor microenvironment to orchestrate ACD in CSCs. We explore how this process contributes to tumor heterogeneity, therapy resistance, and the emergence of quiescent, drug-tolerant CSCs across multiple malignancies, including brain, breast, colorectal, and hematologic cancers. Importantly, we highlight recent efforts to pharmacologically disrupt or redirect ACD using inhibitors of NOTCH, WNT, AURORA kinases, and MSI1, presenting ACD as a therapeutic vulnerability rather than a static trait. By shifting the focus from CSC markers to division mode, this review introduces a novel conceptual framework for targeting tumor hierarchy and plasticity. Understanding and manipulating ACD offers a promising frontier in precision oncology - one where altering the balance of cell fate decisions could limit relapse, reduce intratumoral complexity, and enhance long-term treatment outcomes.