Proteogenomic profiling of soft tissue leiomyosarcoma reveals distinct molecular subtypes with divergent outcomes and therapeutic vulnerabilities.

Soft tissue leiomyosarcoma (STLMS) is an aggressive malignancy lacking validated molecular subclassification and effective targeted treatments. We performed comprehensive proteogenomic analysis of primary and metastatic STLMS to uncover biological traits and therapeutic weaknesses. Integrative proteomic and phosphoproteomic analyses using non-negative matrix factorization identified three subtypes. Subtype P1 shows genomic stability, low proliferation, and enrichment of FGFR2 and PDK signaling pathways. Subtype P2 exhibits chromosomal instability, inflammatory programs, activation of CDK-AURKA/B-mTOR/ERK kinome with IGF1R/PDGFRA gene alterations, and poorest survival outcomes. Subtype P3 is highly proliferative, with E2F/DNA-repair programs, elevated NCOR1, and shift towards nonhomologous end joining with upregulation of PARP1. Homologous recombination deficiency (HRD) analysis distinguishes HRD-low P1 from HRD-high P2/P3. Paired analyses suggest HRD increases in metastases within P3. Immune profiling shows P2 as immunosuppressive, characterized by LGALS9 and M2 macrophages. Our proteogenomic analyses provide a molecular landscape of LMS, revealing biological insights, patient outcome stratification, and therapeutic targets.