Background <p>Breast cancer (BRCA) remains a major global health challenge due to its high recurrence rates and resistance to therapy, underscoring the need for reliable biomarkers and novel therapeutic targets. Tripartite motif-containing protein 2 (TRIM2), an E3 ubiquitin ligase, has been implicated in tumorigenesis across multiple cancers, yet its role in BRCA remains poorly understood.</p> Methods <p>We integrated multi-omics datasets from TCGA, GEO, and METABRIC, and validated TRIM2 expression using proteomic data from the Proteomic Data Commons and Human Protein Atlas. Single-cell RNA sequencing was employed to characterize the transcriptional heterogeneity and cell–cell interaction patterns of TRIM2⁺ tumor cells. Ubiquitin-proteomic and proteomic profiling were conducted to identify TRIM2-regulated substrates. Drug sensitivity prediction and molecular docking were applied to assess TRIM2-related therapeutic responses, and in vitro experiments were performed to validate its biological functions.</p> Results <p>We found that TRIM2 is consistently downregulated in BRCA tissues at both transcriptomic and proteomic levels, with low expression significantly associated with advanced stage and poor overall survival. Clinically, elevated TRIM2 expression correlated with improved responsiveness to immunotherapy. Drug sensitivity and molecular docking analyses identified 64 TRIM2-sensitive compounds, including five with strong binding affinities, suggesting potential for targeted therapeutic development. Genomic alterations and promoter hypermethylation were identified as potential mechanisms driving TRIM2 dysregulation. Multi-layered functional enrichment analyses, including transcriptomic, proteinomic, and ubiquitin-proteomic profiling, suggested that TRIM2 regulates cancer- and immune-related pathways including TGF-β, Hippo, TNF, and IL-17 signaling pathways. Single-cell RNA sequencing further demonstrated that TRIM2⁺ and TRIM2⁻ tumor cell subpopulations engage in distinct cell–cell interactions, highlighting TRIM2’s role in shaping tumor-immune communication. Functional assays confirmed that TRIM2 suppresses BRCA cell proliferation and anchorage-independent growth in vitro. Immune profiling revealed that high TRIM2 expression is associated with enhanced immune checkpoint activity, greater infiltration of antitumor immune cells, and increased immune recruitment scores.</p> Conclusions <p>Collectively, our findings identify TRIM2 as a potential tumor suppressor and novel prognostic biomarker in BRCA, with potential utility for guiding personalized immunotherapy and targeted treatment strategies.</p>