Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance

Abstract Background and Rationale Synthetic lethality (SL)‐based strategies hold significant promise for overcoming therapeutic resistance, a critical bottleneck in cancer treatment where cancer cells evade anticancer therapies, leading to diminished efficacy or treatment failure. The core of SL lies in exploiting tumour‐specific vulnerabilities: drug‐resistant cells often acquire unique genetic defects or compensatory adaptive responses, and SL strategies selectively target genes or pathways dependent on these vulnerabilities to induce specific cell death, thereby reversing resistance. Content and Focus This review systematically elaborates on SL mechanisms and the multi‐faceted nature of tumour drug resistance, then focuses on how SL counteracts resistant phenotypes by leveraging resistant cells’ vulnerabilities. We further delineate SL applications in preclinical resistance models, highlight representative SL‐related drugs and predictive biomarkers and critically analyse challenges in clinical translation. Conclusion By integrating mechanistic insights, preclinical validation and translational perspectives, this review aims to provide novel insights for precision therapy and a foundational reference to advance SL strategies in overcoming tumour resistance and facilitating their clinical implementation. Key points SL‐based strategies exploit tumour‐specific vulnerabilities in drug‐resistant cells to induce selective cell death and overcome therapeutic resistance. This review dissects SL mechanisms, diverse drivers of tumour drug resistance and how SL counteracts resistant phenotypes via these vulnerabilities. It summarises clinical translational applications of SL from preclinical studies to trials, approvals and emerging targets, and discusses future precision therapy.