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Life sciences · Journal article
Frontiers in Immunology · October 12, 2026
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Immune checkpoint blockade improves outcomes in defined settings of triple-negative breast cancer (TNBC), but treatment failure does not identify a single biological mechanism or an interchangeable set of remedies. This focused narrative review examines how biomarkers can distinguish established treatment eligibility from investigational strategies intended to address immune exclusion and resistance. Randomized TNBC trials provide the clinical reference, while translational studies and trials in other malignancies are classified according to their applicability. PD-L1 testing remains relevant to first-line pembrolizumab combinations in advanced TNBC; it is not required to select patients for the KEYNOTE-522 early-stage regimen. Sacituzumab govitecan plus pembrolizumab is a United States-approved first-line option for PD-L1-positive advanced disease, but its comparative benefit establishes regimen-level efficacy rather than immunological synergy or reversal of checkpoint resistance. Proposed immune-priming effects remain specific to the ADC, experimental model and disease setting and should not be generalized across the ADC class. Stromal lymphocytes, spatial immune organization and circulating tumor DNA provide complementary biological or prognostic information without establishing a general replacement for PD-L1 or a validated rule for treatment escalation or omission. Strategies involving epigenetic modulation, adenosine blockade, DNA-damage signaling and local immune priming show different levels of evidence, including negative randomized findings. Particular caution is needed when extrapolating antigen-density thresholds and cellular-therapy outcomes from hematological malignancies. A useful biomarker framework must specify the disease setting, assay, proposed action and evidence that changing treatment improves outcomes. Prospective testing of these links, together with regimen-specific safety assessment and reliable access to established diagnostics, is necessary before resistance-directed combinations can be implemented routinely.