Exploring ULK family in human cancer: insights into mechanisms and therapeutic potential

The ULK (Unc-51-like kinase) family, a group of serine/threonine protein kinases, plays a central regulatory role in the initiation of autophagy. Autophagy has a dual role in cancer, as it can both inhibit tumor formation and promote the survival and progression of established tumors, making targeting autophagy an attractive therapeutic strategy for cancer. This review systematically explores the expression, function, and molecular mechanisms of the ULK family (including ULK1, ULK2, ULK3, ULK4, and SKT6) in various human cancers. Studies have shown that ULK family members play complex and sometimes contradictory roles in different cancer types and histological backgrounds, functioning as both tumor suppressors and oncogenes. Their functions are precisely regulated through multiple signaling pathways, such as mTOR and AMPK, and influence key cancer characteristics, including cell survival, proliferation, metabolic adaptation, metastasis, and drug resistance. Additionally, this review focuses on the latest progress in targeting the ULK family (particularly the development of selective ULK small molecule inhibitors) and their therapeutic potential as monotherapies or in combination with chemotherapy, targeted therapy, and immunotherapy. Despite challenges, such as understanding their context-dependent functions and refining biomarkers, targeting the ULK family, which represents the initiation step of autophagy, opens up a promising path for the development of novel anti-cancer therapies.