Synergistic attack of “old drugs for new uses”: repositioning strategies in cancer combination therapy

Cancer treatment faces severe challenges such as drug resistance, side effects, and high costs. The “repurposing old drugs” strategy, which involves repositioning approved drugs for non-oncology indications for cancer treatment, has opened up new avenues for developing efficient, low-toxicity, and rapidly translatable combination therapies. This strategy can not only accelerate clinical translation by leveraging known pharmacological and safety data but also generate synergistic effects with standard chemotherapy, targeted therapy, or immunotherapy by targeting non-classical pathways such as the tumor microenvironment, metabolic reprogramming, and epigenetic regulation. This paper aims to systematically review the repositioning strategies of non-oncology drugs in cancer combination therapies, focusing on their mechanisms of action, synergistic principles, high-throughput screening and computational prediction methods, as well as pre-clinical and clinical research progress based on models such as patient-derived organoids. The paper systematically analyzes the synergistic effects and potential of representative drugs such as metformin, statins, antimalarials, antipsychotics, non-steroidal anti-inflammatory drugs, β-blockers, antihistamines, and cardiovascular drugs. It also summarizes the current challenges in drug screening, mechanism validation, commercial incentives, clinical trial design, and safety re-evaluation, aiming to provide a theoretical basis and future research directions for optimizing cancer combination treatment strategies.