Strategies to enhance selectivity include (i) biomarker-based enrichment (e.g. BRCA/HRD, ATM loss, MSI-H for WRN inhibition); (ii) synthetic-lethality pairing to reduce dose intensity (e.g. ATR+PARP, POLθ+PARP, DNA-PKcs+radiation); (iii) intermittent/scheduled dosing to exploit tumor repair liabilities while allowing normal-tissue recovery; (iv) tumor-directed delivery and CNS-penetrant design where needed; and (v) immune-oncology combinations, as persistent DNA damage can activate cGAS–STING, increasing immunogenicity but also necessitating vigilance for immune-related adverse events. Here, CGAS is linked to neoplasm.