Targeting frizzled receptors (FZDs) for anti-tumor therapy: From orthosteric to allosteric inhibition

Frizzled receptors (FZDs) have emerged as pivotal regulators in cancer biology, orchestrating key oncogenic processes such as tumor metastasis, therapy resistance, and stemness through canonical WNT/ β -catenin and noncanonical WNT/PCP and WNT/Ca 2+ signaling pathways. Their overexpression in diverse malignancies and cell surface localization make FZDs compelling therapeutic targets. Yet, clinical translation of FZD-targeted therapies has been hindered by limited efficacy and poor subtype specificity of FZD orthosteric inhibitors. In this review, we provide a comprehensive and systematic analysis of FZD biology by tracing its discovery history, elucidating its conserved structural features, and deciphering its context-dependent roles in WNT signaling. We propose novel insights into the multifaceted roles of FZD in tumorigenesis, positioning it as a driver of cancer progression. We emphasize the urgent need for developing subtype-selective targeting strategies for FZD, critically assess the challenges of achieving binding specificity within highly homologous extracellular domains, and summarize cutting-edge advances in structure-based design of FZD negative allosteric modulators. This study establishes a strategic framework for precision targeting of the FZD family, paving the way for developing more efficient, mechanism-driven, and potentially transformative anticancer therapies.