Synthetic lethality and DNA damage response targeting in cancer stem cells: a comprehensive review.

This comprehensive review explores the critical intersection of Synthetic Lethality (SL) and DNA Damage Response (DDR) targeting within Cancer Stem Cells (CSCs), a subpopulation central to tumor initiation, metastasis, and therapeutic resistance. CSCs exhibit unique biological properties, including enhanced DNA repair mechanisms and metabolic plasticity, rendering them intrinsically resistant to conventional therapies. The fundamental mechanisms of DDR pathways and their dysregulation in cancer are delineated, highlighting how these vulnerabilities can be exploited through SL. The review synthesizes current preclinical and clinical advancements in targeting CSCs via DDR inhibitors, including PARP, ATR, ATM, and DNA-PKcs inhibitors, as well as emerging SL targets. Furthermore, advanced therapeutic modalities such as small molecule inhibitors, antibody-drug conjugates, CAR cell therapies, glycan-based approaches, and nanoparticle delivery systems tailored for CSC elimination are discussed. Finally, persistent challenges, including CSC heterogeneity, the immunosuppressive tumor microenvironment, on-target/off-tumor toxicities, and translational hurdles, are addressed, emphasizing the transformative potential of integrated diagnostic platforms leveraging AI, liquid biopsy, multi-omics, and single-cell profiling to usher in a new era of precision oncology for durable cancer control.