Tumor Microenvironment-Mediated Resistance in HER2-Positive Breast Cancer: Recent Advances and Therapeutic Challenges

Abstract

: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is associated with aggressive disease and poor prognosis. Despite advances in HER2-targeted therapies, resistance remains a major clinical challenge. This review focuses on the mechanisms of resistance to HER2-targeted therapies, with particular emphasis on the tumor microenvironment (TME). The TME, composed of immune cells, cancer-associated fibroblasts (CAFs), and extracellular matrix components, significantly influences therapeutic responses. Immunosuppressive cells such as tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) contribute to immune evasion and therapeutic resistance. Additionally, CAFs contribute to resistance by remodeling the extracellular matrix and creating physical barriers that restrict drug delivery and immune cell infiltration. Emerging therapeutic strategies targeting the TME components show promise in overcoming resistance and improving treatment outcomes. The development of predictive biomarkers, particularly those reflecting TME components, and the integration of spatial profiling technologies will be critical in optimizing personalized treatment strategies for HER2-positive breast cancer.