INTRODUCTION: Soft tissue sarcomas (STS) are a group of rare malignancies with limited treatment options and a persistent lack of effective therapies. Despite the heterogeneous nature of STS, the canonical WNT/β-catenin signalling pathway has been associated with sarcomagenesis, and also with the initiation and progression of other cancers. METHODS: Eight patient-derived primary cultures representing different STS histological subtypes were characterized by immunohisto(cyto)chemistry, WNT/β-catenin activation, and Next-Generation Sequencing (NGS). RESULTS: Elevated levels of active phospho-β-catenin and its nuclear localization was found in all STS primary cultures, with heterogeneous downstream WNT signaling activation. Genomic analysis of matched STS tumors identified pathogenic or likely pathogenic genetic variants in crucial signaling pathways, including WNT, DNA damage repair and PI3K/AKT/mTOR-MAPK pathways. Interestingly, 50% of STS tumors studied carried genetic variants in PIK3CA and PTEN genes with potential clinical significance, listed as predictive biomarkers of response to specific drugs (FDA-level 3). CONCLUSIONS: This study provides valuable insights into WNT signaling vulnerabilities in STS, offering a foundation for the development of targeted therapeutic strategies and the identification of potential biomarkers for personalized treatment approaches in this challenging group of malignancies.