Programmed death ligand 1 and the tumor microenvironment shape immune checkpoint combination therapy in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a clinically aggressive and molecularly heterogeneous subtype in which immune checkpoint blockade produces meaningful but inconsistent benefit. Programmed death-ligand 1 (PD-L1), expressed across malignant and immune-cell compartments, functions through programmed cell death protein 1 (PD-1) within a tumor microenvironment that can either sustain antitumor immunity or promote immune escape. This review critically integrates TNBC molecular heterogeneity, PD-1/PD-L1 signaling, microenvironmental regulation, resistance mechanisms, predictive biomarkers, safety, and clinical evidence for PD-L1-directed therapy. Unlike drug-centered summaries, it links divergent clinical outcomes to chemotherapy backbone, disease setting, biomarker assay, and immune context. Comparative analysis of the IMpassion trials indicates that efficacy cannot be attributed to the antibody alone. Tumor-infiltrating lymphocytes, cancer-associated fibroblasts, tumor-associated macrophages, tumor-associated neutrophils, and myeloid-derived suppressor cells form interacting networks that shape PD-L1 expression, immune exclusion, and adaptive resistance. Emerging strategies include bispecific antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or lymphocyte activation gene 3 (LAG-3) alongside PD-L1; co-blockade of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) or T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT); sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9)-directed macrophage approaches; and cellular therapies. Current evidence favors integrated biomarkers rather than PD-L1 staining alone, combining assay-defined PD-L1 status with immune-cell composition, molecular subtype, and dynamic markers such as circulating tumor DNA. The central clinical challenge is to identify the patients, disease settings, and combinations in which therapeutic benefit outweighs toxicity and resistance.