Multi-omics profiling uncovers immune-molecular clusters with distinct chemo-immunotherapeutic vulnerabilities in a mouse model of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of breast cancer with limited treatment options. Predicting patient response to chemo-immunotherapy remains challenging, highlighting the need for stratification. Here, we performed an integrative multi-parametric analysis combining histological, genomic, transcriptomic, proteomic, and immune profiling in the immunocompetent MMTV-R26Met TNBC mouse model and matched outcomes with patient data. We uncovered four distinct TNBC clusters defined by unique intrinsic (molecular/genomic) and extrinsic (immune) features that closely parallel patient subtypes. We established syngeneic graft models faithfully recapitulating both molecular and immune hallmarks of primary tumors, emphasizing their translational relevance. Strikingly, in vivo evaluation of combined chemotherapy (epirubicin) and anti-PD-1 immunotherapy revealed cluster-specific therapeutic vulnerabilities associated with molecular and immune traits. Findings document how TNBC response is shaped by both tumor-intrinsic and immune features. Our study provides a robust preclinical platform for precision immuno-oncology, enabling stratification of TNBC patients for tailored onco-immunotherapies. Overall design: mRNA of a total of 4 tumoral breast from MMTV mice were submitted for bulk RNA-sequencing.