PTBP1 drives immune dysfunction and predicts immunotherapy response in metastatic triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a subtype with limited treatment options and poor outcomes, particularly in the metastatic setting. Although immunotherapy has shown efficacy in early-stage disease, its benefit remains suboptimal in women with locally advanced and metastatic TNBC. Here, we identify the splicing factor PTBP1 as a tumor-intrinsic regulator of immune evasion in metastatic TNBC. By integrating clinical, single-cell, and bulk transcriptomic data with multiplex immunohistochemistry, CRISPR-Cas9 genome editing, and functional assays, we show that PTBP1 impairs antigen presentation, promotes T cell dysfunction, and is associated with worse outcomes, independent of tumor-infiltrating lymphocyte levels. Furthermore, CRISPR-mediated silencing of PTBP1 restores HLA expression and reactivates antigen presentation pathways in TNBC. PTBP1 expression is elevated in metastatic compared to primary TNBC tumors and correlates with immune dysfunction signatures. Consistently, in the phase II TONIC clinical trial, metastatic TNBC patients with PTBP1-high tumors had poor response and shorter survival following PD-1 blockade, and PTBP1 expression showed a predictive performance comparable to PD-L1 and TILs in this cohort. These findings position PTBP1 as a tumor-intrinsic regulator of immune evasion and a potential biomarker to inform immunotherapy strategies in metastatic TNBC.