Modulation of tumor-associated lymphangiogenesis by combination immunotherapy approaches in triple-negative breast cancer: a systematic review

Background: Treatment for triple-negative breast cancer (TNBC) is challenging due to its aggressive nature and its high metastatic potential. This breast cancer subtype is characterized by the presence of highly proliferative cells with great ability to promote lymphangiogenesis and facilitate metastasis to regional lymph nodes (LNs). Indeed, the physical presence of breast cancer cells in regional LNs is an important prognostic factor. Moreover, tumor-associated lymphangiogenesis within the TNBC microenvironment plays a crucial role not only providing new routes for the metastatic spread of cancer cells but also delineating tumor immunity. As such, modulating tumor-associated vasculature by combination immunotherapy could be a promising strategy to treat TNBC. Methods: In this study, we have conducted a comprehensive review of previously published works using PubMed and Web of Science databases for studies addressing immunotherapy and lymphangiogenesis in TNBC. Inclusion criteria were applied to identify relevant preclinical and clinical studies focusing on the intersection of immune-based therapies and the tumor lymphatic network. A total of 59 eligible articles were identified and analyzed. Results: Our findings indicate that, while immunotherapy is an effective clinical strategy to treat TNBC, current strategies rarely incorporate agents targeting tumor-associated lymphangiogenesis. The reviewed studies suggest that lymphatic vessels within the TNBC microenvironment are not only structural pathways for metastasis but also dynamic regulators of immune cell trafficking and tumor immune evasion. Despite this, the therapeutic potential of combining immunotherapy with lymphangiogenesis-targeting agents remains underexplored. Conclusion: Despite clear evidence supporting the role of lymphangiogenesis in TNBC progression and immune regulation, its integration into immunotherapy regimens remains largely unexplored. Therefore, the development of novel combination strategies based on immunotherapy and agents targeting lymphatic vessels and their crosstalk with immune and cancer cells within the TNBC microenvironment would greatly improve the response of TNBC patients to immunotherapy.