The role of FK506-binding protein 12 in cancer: from biology to clinical application.

FK506 binding proteins (FKBPs) are highly conserved members of the immunophilin family, playing crucial roles in inflammation, immune responses, tumor biology, and developmental signaling pathway. Among these, FK506-binding protein 12 (FKBP12) is the smallest and is renowned for its direct binding to tacrolimus (FK506) and sirolimus (rapamycin). FKBP12 is well-established in mediating drug-protein interactions, neurodegenerative diseases, immune-related processes, and inflammatory signaling pathways. Although accumulating evidence suggests that FKBP12 is associated with numerous tumor-related signaling pathways, its precise role in cancer remains unclear. In this review, we provide a comprehensive overview of the biology and functions of FKBP12, with a particular focus on its mechanisms in malignancies, emphasizing its dual role in oncogenesis. A thorough understanding of this paradox is essential for the development of targeted therapies. We also highlight the clinical applications of FKBP12 in oncology, including its therapeutic potential, diagnostic, and prognostic significance, particularly in relation to its dual role. Finally, we address the contradictory functions of FKBP12 in various cancers and attempt to elucidate the underlying reasons. We also explore the relationship between FKBP12 and tumor microenvironment, aiming to shed new light on the potential role of FKBP12 as a novel immunotherapy target in cancer. We believe this review will be helpful to create second-generation drugs targeting FKBP12 with higher selectivity and fewer complications in the future.