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The addition of immune checkpoint inhibitors (ICIs) to frontline chemotherapy has improved survival for patients with advanced triple-negative breast cancer (TNBC) expressing programmed death-ligand 1 (PD-L1). Nonetheless, most patients develop resistance, with outcomes remaining poor for this population. Moreover, unsatisfactory activity has been observed with ICIs in PD-L1-negative TNBC and in other breast cancer (BC) subtypes, warranting a deeper understanding of resistance to ICIs in BC. We discuss the immune landscape of distinct BC subtypes, review the clinical activity of immunotherapy in BC, and highlight strategies under development to overcome resistance to ICIs. Activity and resistance to ICIs in BC are strongly related to the intrinsic immunophenotype of the tumor tissue. Several promising biomarkers reflecting the immunological state of BC are emerging, with only PD-L1 expression currently adopted into clinical practice. However, limitations make of PD-L1 a sub-optimal biomarker for patient selection, which require efforts to integrate this marker with other immunological features. Concomitantly, a wide variety of drug combinations designed to overcome immune-resistance are being evaluated, with some encouraging signals observed in early-phase trials. Combination strategies tailored to patient and tumor immunophenotype may allow to overcome resistance and fully exploit the potential of ICIs.

Understanding resistance to immune checkpoint inhibitors in advanced breast cancer