LSM4 drives the progression of triple-negative breast cancer through alternative splicing

Triple-negative breast cancer (TNBC) remains a therapeutic challenge due to its aggressive nature and limited treatment options. Through integrated genomic and proteomic profiling, we identified the RNA-binding protein LSM4 as a key driver of TNBC progression. LSM4 was significantly upregulated in TNBC tissues and showed progressively increasing expression from normal breast epithelial cells to highly aggressive cancer models. Functional genomics using CRISPR screening nominated LSM4 as a functionally essential spliceosomal gene among nine critical candidates. Genetic suppression of LSM4 in TNBC cell lines (MDA-MB-231 and CA1a) markedly inhibited malignant phenotypes including proliferation, migration, invasion, and colony formation. RNA-sequencing analysis demonstrated that LSM4 knockdown alters 1,593 alternative splicing events, predominantly through exon skipping, and disrupts genes involved in key cancer pathways including RNA degradation. We established an LSM4-associated gene signature that correlated with an immunosuppressive microenvironment characterized by altered expression of immune markers and checkpoint molecules. Clinical validation using the FUSCC cohort revealed that this signature strongly predicted poor overall survival (p = 0.00067), recurrence-free survival (p = 0.05), and distant metastasis-free survival (p = 0.0092). Our findings establish LSM4 as an important splicing regulator in TNBC, linking spliceosomal dysfunction to tumor progression and immune evasion, and nominate LSM4 as a promising prognostic biomarker and therapeutic target.