Roles of FEN1 in tumor biology: Mechanisms, therapeutic implications, and emerging strategies

Flap endonuclease 1 (FEN1), a multifunctional, structure-specific nuclease critical for DNA replication and repair, has emerged as a pivotal player in tumor biology. Multiple mutations and genetic polymorphisms in FEN1 are linked to cancer predisposition and genomic instability across various malignancies. Furthermore, aberrant overexpression of FEN1 correlates with tumor initiation, aggressive progression, and poor prognosis in diverse cancers. Accumulating evidence demonstrates that suppressing FEN1 expression or activity sensitizes cancer cells to conventional therapies (chemotherapy and radiotherapy), molecularly targeted agents, and emerging immunotherapies, such as chimeric antigen receptor T-cell (CAR-T) therapy, suggesting its broad utility in overcoming treatment resistance. Additionally, developing small-molecule FEN1 inhibitors and synthetic-lethal interactions between FEN1 and additional DNA-repair genes could guide the development of precision combination therapies. By exploiting FEN1's unique substrate recognition properties, early-stage cancers can be detected via liquid biopsy or protein-focused assays. Collectively, this review underscores FEN1 as a promising biomarker and a multifaceted target for cancer interception and treatment, while also emphasizing the need for further mechanistic exploration and translational validation of FEN1-directed strategies.