A new combined immunotherapy strategy for triple-negative breast cancer

Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor, progesterone receptor, and HER2, represents 5%-20% of breast cancers and is associated with aggressive clinical behavior, early recurrence, and poor prognosis. The lack of actionable targets has historically made chemotherapy the cornerstone of systemic therapy, albeit with limitations due to toxicity and acquired resistance. The advent of immune checkpoint inhibitors (ICIs), particularly agents targeting the PD-1/PD-L1 axis, has revolutionized the therapeutic landscape for TNBC. This subtype exhibits a comparatively higher level of immunogenicity, often featuring a tumor-infiltrating lymphocyte-rich microenvironment, which provides a rationale for immunotherapy. However, single-agent ICI response rate remains modest, driving the development of combination strategies to synergistically enhance anti-tumor immunity. Immunotherapy combined with chemotherapy has established a new standard of care. Chemotherapy not only exerts direct cytotoxic effects but also can induce immunogenic cell death, promoting antigen presentation and T-cell activation. In the neoadjuvant setting for early-stage, high-risk TNBC, the KEYNOTE-522 trial demonstrated that adding pembrolizumab to chemotherapy significantly improved pathological complete response (pCR) rate and event-free survival (EFS), leading to its regulatory approval. Similarly, in metastatic TNBC, both the IMpassion130 (atezolizumab+nab-paclitaxel) and KEYNOTE-355 (pembrolizumab+chemotherapy) trials established overall survival benefits for PD-L1-positive patients, solidifying the role of chemoimmunotherapy in the first-line setting. PD-L1 expression remains a key, albeit imperfect, predictive biomarker. The combination of ICIs with targeted therapies represents a highly promising frontier. For patients with germline BRCA1/2 mutations, poly ADP-ribose polymerase (PARP) inhibitors like olaparib induce synthetic lethality and may enhance tumor immunogenicity via the cGAS-STING pathway. Early clinical data suggest encouraging activity for PARP inhibitor-ICI combinations. Furthermore, antibody-drug conjugates (ADCs) are redefining treatment paradigms. Sacituzumab govitecan, a Trop-2-directed ADC, improves survival in pretreated metastatic TNBC. Notably, the HER2-directed ADC trastuzumab deruxtecan demonstrates potent activity even in tumors with low HER2 expression (HER2-low), a category encompassing many TNBCs. Its ″bystander effect″ allows for cytotoxic payload delivery to antigen-heterogeneous tumors, creating potential for synergy with ICIs. Other combinations under investigation include ICIs with anti-angiogenic agents (e.g., bevacizumab) which may normalize vasculature and alleviate immune suppression, and those with tyrosine kinase inhibitors (e.g., lenvatinib) or CDK4/6 inhibitors which possess immunomodulatory properties. Despite significant progress, major challenges persist. Predictive biomarkers beyond PD-L1, such as integrated multi-omics profiles, dynamic immune cell monitoring, and gut microbiome analysis, are needed for better patient stratification. Mechanisms of primary and acquired resistance, involving upregulation of alternative immune checkpoints (e.g., LAG-3, TIM-3), expansion of immunosuppressive cells (e.g., MDSCs), and loss of antigen presentation, require further elucidation. Strategies to overcome resistance include next-generation bispecific antibodies and agents targeting the immunosuppressive tumor microenvironment. Furthermore, managing the overlapping toxicities of combination regimens remains a critical clinical consideration. In conclusion, immunotherapy-based combinations have fundamentally transformed TNBC management, moving it from a chemotherapy-centric model into a new combination era. While immuno-chemotherapy is now standard, combinations with targeted agents like PARP inhibitors and ADCs show immense potential. Future efforts must focus on optimizing combination strategies through a deeper understanding of the tumor-immune cycle, developing refined predictive biomarkers, and carefully balancing efficacy with toxicity to realize the goal of personalized and durable treatment responses for TNBC patients.