UPS are a heterogenous group of poorly differentiated tumors. We hypothesized that there is a link between dedifferentiation state of UPS and immune infiltrate and that this relationship relies on specific pathways activation and related genomics alterations with potential therapeutic impact. Main objectives were to generate a comprehensive Omics landscape of true UPS and test potential targets for therapeutics approach on cell lines and patient tumour derived mouse xenografts (PDX). We analysed 135 UPS cases, 25 of which were selected for full exome and RNA sequencing, proteomics profiling conducted by data-independent acquisition mass spectrometry, as well as immune profiling by immunohistochemistry (IHC). Using unsupervised consensus clustering and hierarchical clustering of RNA-sequencing, we identified two main groups of patients: group A and B, with associated gene clusters. Group A was mainly enriched in genes that play a crucial role in both normal development and stemcellness, notably FGFR2. Group B was strongly enriched in genes involved in immunity. Using proteomics analysis we found two main proteomic groups - PA and PB – that highly correlated with the two main genetic groups - A and B. The proteome group PB, associated with the immune-high group B, was significantly enriched in immune response pathways, whereas the proteome group PA, associated with the immune-low group A, was mainly enriched in MYC targets and epithelial mesenchymal transition pathways. We then further assessed the therapeutic potential of this classification by using in vitro and in vivo PDX models directly derived from patient tumor samples from the molecular profiling study. We showed robust anti-tumor activity of FGFR2 inhibitor JNJ-42756493 and of NEO2734, a first-in-class epigenetic modifier that notably inhibits Bromodomain and Extra-Terminal domain (BET) family and Cyclic AMP response element binding protein (CREB)-binding (CBP) proteins, in models from group A, selectively. This integrated analysis of UPS allowed the identification of two main entities with distinct molecular features, immune phenotypes, as well as differential sensitivity to specific anti-cancer agents. The authors. La Ligue. All authors have declared no conflicts of interest.