Molecular subgroups and biomarker guided precision immunotherapy in triple-negative breast cancer: advances, challenges, and future directions

Abstract

Triple-negative breast cancer is an aggressive, biologically heterogeneous subtype with limited targeted therapies. Immunotherapy improves outcomes in selected patients, but durable benefit is limited by inter- and intratumoral heterogeneity, imperfect biomarkers, and primary or acquired resistance. This review integrates evidence from major positive and negative trials, molecular subgroup studies, predictive biomarkers, and tumor immune microenvironment research to assess current standards and unresolved challenges. Immune checkpoint blockade plus chemotherapy is now standard for high-risk early-stage TNBC and PD-L1-positive metastatic disease, although benefit varies by disease setting, assay, and immune phenotype. Biomarkers such as PD-L1 and tumor-infiltrating lymphocytes provide useful but incomplete guidance because of methodological differences, spatiotemporal heterogeneity, and treatment-induced changes. The central clinical challenge is to identify which patients require intensified immune-based combinations and which are unlikely to benefit from checkpoint blockade alone. We propose a precision immunotherapy framework that integrates TNBC molecular subgroups, validated and dynamic biomarker models, rational combinations, resistance mechanisms, and emerging tools, including single-cell sequencing, spatial transcriptomics, multi-omics, and AI-assisted stratification. This strategy may improve response durability while reducing unnecessary toxicity.