Nuclear factor of activated T cells as a driver of tumor progression and a target for precision therapy

The Nuclear Factor of Activated T Cells (NFAT) family comprises closely related transcription factors. Numerous biological processes including angiogenesis, invasion, migration, proliferation, and cell survival are regulated by the NFAT family. NFATs are overexpressed and have increased transcriptional activity in a variety of human solid tumors and hematological cancers. Beyond tumor cell-intrinsic roles, NFAT has also emerged as an important regulator of the tumor microenvironment (TME), where it can influence immune cell behavior and contribute to mechanisms of immune evasion. The discovery of the multifaceted functions of NFATs has driven the need to further unveil their role in cancer and provide new insights into other potential roles. This review provides a comprehensive narrative synthesis of current molecular and clinical studies, with particular emphasis on how NFAT shapes tumor immune interactions and modulates the TME. By integrating findings across different cancer types, we highlight how NFAT may contribute to both tumor progression and immune regulation. The review concludes by highlighting significant knowledge gaps and recommending future paths for translational and therapeutic research to leverage NFAT signaling as a potential target in precision cancer therapy.