Abstract
Abstract
PARP inhibitors (PARPi) drive efficacy in BRCA-mutant breast cancer (BC) via DNA damage-induced synthetic lethality and immune activation, supporting their combination with immune checkpoint blockade. In the TALAVE study, patients with advanced BRCA-mutant or wild-type (WT) HER2-negative BC received talazoparib followed by talazoparib plus avelumab. Only BRCA-mutant BC responded clinically. Serial multi-omic profiling revealed BRCA-dependent tumor-immune remodeling, including sustained γH2AX–pTBK1 signaling with increased CD8+ T cells, tumor cell depletion, and enrichment of CD163+ macrophages. In contrast, BRCA-WT tumors remained compact and immunosuppressed with reduced T cells after therapy. PD-1+ T cells localized to CD4+-rich neighborhoods and correlated with longer progression-free survival in BRCA-mutant tumors. However, PD-L1+ cells were rapidly depleted or confined to immune-excluded regions, spatially segregating them from PD-1+ T cells, impairing effective checkpoint blockade. These findings suggest limited benefit of PD-1/PD-L1 blockade in augmenting PARPi activity and highlight the need for alternative strategies to sustain PARPi-induced immunity.