Synthetic lethality in cancer: mechanism exploration and therapeutic applications

Abstract

Synthetic lethality (SL) is a genetic interaction phenomenon in which a cell can survive when either of two genes is individually mutated, but simultaneous disruption of both genes leads to cell death. This phenomenon reveals the redundancy and complementarity among gene functions and provides a theoretical basis for precision cancer therapies targeting specific genetic defects. The SL approach achieves the selective elimination of cancer cells by targeting the synergistic survival pathways on which tumor-specific genetic defects rely. This review highlights the core molecular mechanisms of SL in DNA damage repair, cell cycle checkpoint regulation, metabolic reprogramming, and epigenetic regulation; summarizes target discovery strategies based on high-throughput functional genomics and computational biology; and discusses successful clinical translation cases exemplified by poly(ADP-ribose) polymerase (PARP) inhibitors, along with current challenges and future directions.