Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer representing approximately 25 % of all uterine malignancies. The molecular heterogeneity and pathogenesis of uLMS are not well understood, and translational studies aimed at discovering the vulnerabilities of this tumor type are of high priority. We conducted an innovative comprehensive multi-omics integration study from DNA to protein using freshly frozen tumors. Here, we show that two tumors harbor actionable therapeutic targets, IDH1_p.Arg132Cys and KRAS_p.Gly12Cys, and homologous recombination deficiency (HRD) is the most predominant genomic signature. Additionally, 80 % of the samples presented a chromothripsis signature, reinforcing the aneuploidy phenotype of these tumors. Tumors with a high proliferation score and high Ki67 expression was associated with worse overall survival (OS). We observed a high frequency of balanced fusion events involving EEF1A1 with enrichment of the EGFR pathway. For the first time, uLMS proteomics analysis showed the enrichment of pathways associated with suppression of the innate immune system and ECM organization. Finally, our comprehensive multi-omics integration analysis identified amplification of the CTHRC1 gene from the matrisome, with a negative impact on OS. Interestingly, the expression of Ki67 and CTHRC1 exhibits a strong negative correlation, underscoring two distinct and mutually exclusive biological profiles in uLMS: (i) highly proliferative tumors, characterized by elevated Ki67 expression, and (ii) tumors driven by ECM remodeling, marked by high CTHRC1 levels. Taken together, this deep functional multi-omics approach contributes to the detection of new molecular features of uLMS and suggests that patients could benefit from precision oncology in clinical practice.