Driving the degradation of oncofusion proteins for targeted cancer therapy

•Oncofusion proteins drive the development of numerous cancers.•Oncofusion proteins present extremely high stability by escaping degradation.•Triggering the degradation of oncofusion proteins has received extensive attention.•Strategies to induce the degradation of several oncofusion proteins have been elucidated.•The exploration of more mechanisms and strategies is the way forward. Oncofusion proteins drive the development of about 16.5% of human cancers, functioning as the unique pathogenic factor in some cancers. The targeting of oncofusion proteins is an attractive strategy to treat malignant tumors. Recently, triggering the degradation of oncofusion proteins has been shown to hold great promise as a therapeutic strategy. Here, we review the recent findings on the mechanisms that maintain the high stability of oncofusion proteins. Then, we summarize strategies to target the degradation of oncofusion proteins through the ubiquitin-proteasome pathway, the autophagy-lysosomal pathway, and the caspase-dependent pathway. By examining oncofusion protein degradation in cancer, we not only gain better insight into the carcinogenic mechanisms that involve oncofusion proteins, but also raise the possibility of treating oncofusion-driven cancer.