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/Ca²⁺ 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.

Frizzled receptor  /  WNT signaling pathway  /  Negative allosteric modulator  /  Orthosteric inhibitors  /  Drug development  /  Targeted therapy  /  Combination therapy  /  Cancer