Synthetic Lethality-Based Targets and Their Exploration in Tumour Combination Strategies

Synthetic lethality (SL) not only addresses the challenge of drug resistance associated with classical targeted therapies but also offers innovative therapeutic approaches for previously ‘undruggable’ targets, such as deletion mutations in tumour suppressor genes. Advances in technology have significantly enhanced our understanding of gene–gene interactions in cancer cells, enabling the identification of synthetic lethal targets and the development of drugs targeting these mechanisms. Following the extensive clinical application of PARP inhibitors—the first synthetic lethal targeted drugs approved for clinical use—emerging targets such as ATR, WEE1 and WRN have demonstrated promising clinical potential. This review examines the functions and molecular mechanisms underlying these targets and discusses recent advancements in the theory of synthetic lethality. Additionally, it emphasises the integration of synthetic lethal drugs with traditional cancer treatments, highlighting the clinical benefits of this combined strategy and its potential to facilitate more precise and individualised cancer treatment modalities in the future.