Targeting minichromosome maintenance proteins in cancer stem cells: mechanisms and therapeutic opportunities.

Cancer stem cells (CSCs) drive metastasis, relapse, and treatment resistance. A subpopulation of CSCs persists in a quiescent G0 state, enabling chemo- and radiotherapy evasion. Importantly, in G0 and early G1, MCM2-7 are either not loaded or not yet activated; helicase activity arises only after CMG assembly at the G1/S transition. The minichromosome maintenance (MCM) family includes the replicative helicase MCM2-7, which functions as part of the CMG (Cdc45-MCM2-7-GINS) to unwind DNA, and the MCM8/9 helicase, which acts primarily in homologous recombination (HR). Dysregulation of these complexes can potentially influence CSC therapy responses through replication stress and DNA damage response pathways. Accordingly, therapies targeting MCM2-7/CMG complexes are expected to act selectively on cells with active replicative helicases, preferentially affecting reactivated CSCs that have re-entered the cell cycle and their proliferating progeny, whereas quiescent G0 CSCs are likely refractory unless combined with strategies that induce controlled cell-cycle re-entry. This review summarizes the roles of MCM proteins in CSC phenotypes and highlights advances in MCM-targeted therapy, with particular focus on structural mechanisms of drug-target interactions to guide development of rational design and clinical translation.