SLFN11, far from being limited to responding to cancer DNA damage.

SLFN11, a member of the evolutionarily conserved SLFN gene family, is an interferon-stimulated early response gene. This review comprehensively explores its multifaceted roles. Structurally, its three distinct domains endow it with diverse functions. Epigenetic modifications, post-translational alterations, and multiple signaling pathways intricately regulate SLFN11 expression and activity. In terms of functions, it plays crucial roles in the DNA damage response during replication stress, distinct from traditional pathways. It also serves as a protector in the antiviral response and a valuable biomarker for predicting the efficacy of DNA-damaging agents and patient prognosis in various cancers. Beyond these, SLFN11 has non-canonical functions, including immune regulation, modulation of oncological behaviors, involvement in apoptosis, protection against proteotoxic stress, and association with Fanconi anemia. Looking ahead, SLFN11 holds great promise as a biomarker for personalized medicine, but challenges like developing accurate detection methods remain. In immunotherapy, understanding its dynamic changes is essential for optimizing treatment. Strategies to overcome SLFN11-low expression, such as epigenetic modulation, also need further investigation, which may open new avenues for disease treatment.