Advancing Breast Cancer Treatment: The Role of Immunotherapy and Cancer Vaccines in Overcoming Therapeutic Challenges.

Breast cancer (BC) remains a significant global health challenge due to its complex biology, which complicates both diagnosis and treatment. Immunotherapy and cancer vaccines have emerged as promising alternatives, harnessing the body's immune system to precisely target and eliminate cancer cells. However, several key factors influence the selection and effectiveness of these therapies, including BC subtype, tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs), PD-L1 expression, HER2 resistance, and the tumor microenvironment (TME). BC subtypes play a critical role in shaping treatment responses. Triple-negative breast cancer (TNBC) exhibits the highest sensitivity to immunotherapy, while HER2-positive and hormone receptor-positive (HR+) subtypes often require combination strategies for optimal outcomes. High TMB enhances immune responses by generating neoantigens, making tumors more susceptible to immune checkpoint inhibitors (ICIs); whereas, low TMB may indicate resistance. Similarly, elevated TIL levels are associated with better immunotherapy efficacy, while PD-L1 expression serves as a key predictor of checkpoint inhibitor success. Meanwhile, HER2 resistance and an immunosuppressive TME contribute to immune evasion, highlighting the need for multi-faceted treatment approaches. Current breast cancer immunotherapies encompass a range of targeted treatments. HER2-directed therapies, such as trastuzumab and pertuzumab, block HER2 dimerization and enhance antibody-dependent cellular cytotoxicity (ADCC), while small-molecule inhibitors, like lapatinib and tucatinib, suppress HER2 signaling to curb tumor growth. Antibody-drug conjugates (ADCs) improve tumor targeting by coupling monoclonal antibodies with cytotoxic agents, minimizing off-target effects. Meanwhile, ICIs, including pembrolizumab, restore T-cell function, and CAR-macrophage (CAR-M) therapy leverages macrophages to reshape the TME and overcome immunotherapy resistance. While immunotherapy, particularly in TNBC, has demonstrated promise by eliciting durable immune responses, its efficacy varies across subtypes. Challenges such as immune-related adverse events, resistance mechanisms, high costs, and delayed responses remain barriers to widespread success. Breast cancer vaccines-including protein-based, whole-cell, mRNA, dendritic cell, and epitope-based vaccines-aim to stimulate tumor-specific immunity. Though clinical success has been limited, ongoing research is refining vaccine formulations, integrating combination therapies, and identifying biomarkers for improved patient stratification. Future advancements in BC treatment will depend on optimizing immunotherapy through biomarker-driven approaches, addressing tumor heterogeneity, and developing innovative combination therapies to overcome resistance. By leveraging these strategies, researchers aim to enhance treatment efficacy and ultimately improve patient outcomes.