Targeting IL27RA Enhances Immunotherapy in Triple‐Negative Breast Cancer by Modulating Tumor Cells and the Tumor Microenvironment

ABSTRACT Immune checkpoint blockade (ICB) has improved outcomes for patients with triple‐negative breast cancer (TNBC), yet resistance remains widespread and its molecular basis is not fully understood. Through single‐cell RNA sequencing (scRNA‐seq) of paired pre‐ and post‐treatment tumor samples from patients who failed to achieve pathological complete response (non‐pCR) after neoadjuvant PD‐1 therapy, we identified a marked upregulation of interleukin‐27 receptor subunit alpha (IL27RA) in malignant epithelial cells within residual lesions. Integration with scRNA‐seq profiles from an independent cohort of three pCR patients showed that this IL27RA upregulation in malignant epithelium is largely restricted to non‐pCR residual tumors, and high IL27RA expression correlated with poor survival in TNBC cohorts. Mechanistically, IL27RA suppresses MHC‐I expression by activating the PI3K/AKT pathway—rather than the classical IL‐27/STAT axis—thereby impairing CD8⁺ T‐cell cytotoxic function. Inhibition of AKT reversed this phenotype and restored antigen‐specific killing. In orthotopic tumor models, mimicking systemic loss of Il27ra significantly reduced tumor growth and prolonged survival in immunocompetent mice, with single‐cell profiling indicating enhanced intratumoral T‐cell and NK‐cell effector activity. Collectively, our findings identify an epithelial‐intrinsic IL27RA–PI3K/AKT–MHC‐I axis as a central driver of immune evasion and ICB resistance in TNBC and support IL27RA as a promising therapeutic target for overcoming immunotherapy resistance.