Preclinical-Clinical Discrepancies in Immune Checkpoint Inhibitor Efficacy for Triple-Negative Breast Cancer: Disease Stage, Antibody Properties, Biomarker Alignment, and Model Limitations.

Immune checkpoint inhibitors (ICIs) have emerged as an important class of cancer immunotherapies, yet clinical outcomes do not always align with findings from preclinical studies. This review examines preclinical-clinical discrepancies in ICI efficacy for triple-negative breast cancer (TNBC), with a focus on disease stage, antibody properties, biomarker alignment, and model limitations. Preclinical and clinical findings are most concordant in early-stage TNBC, where ICI-based chemoimmunotherapy improves therapeutic outcomes. In contrast, clinical benefit in metastatic TNBC is more limited and biomarker-dependent, while preclinical studies evaluating ICIs in metastatic TNBC remain scarce, limiting our understanding of immunotherapy resistance at this stage. Currently available TNBC models have not been fully leveraged to represent metastatic disease, in part because their immunosuppressive and metastatic progression has not been systematically characterized. Not all TNBC cell lines develop robust spontaneous metastasis in mouse models, and commonly used experimental metastasis models bypass key stages of primary tumor-immune interaction and metastatic evolution within a systemically immunosuppressive host environment. Additional translational gaps further complicate interpretation, including differences in the immune-effector functions of ICI antibodies used in clinical versus preclinical studies and the lack of standardized approaches to correlate PD-L1 expression in mouse model-derived tumors with clinically defined PD-L1 positivity in patient tumors. Recognizing and addressing these gaps will improve preclinical model selection, strengthen interpretation of ICI efficacy data, and enhance the translational value of preclinical studies for advanced TNBC.