Research Advances in Drug Resistance Mechanisms to Anti-HER2 Therapy in HER2-Positive Breast Cancer

HER2-positive breast cancer accounts for 15–20% of all breast cancer cases. Although the development of monoclonal antibodies (e.g., trastuzumab, pertuzumab), tyrosine kinase inhibitors (e.g., lapatinib, pyrotinib), and antibody-drug conjugates (e.g., T-DM1, trastuzumab deruxtecan) has greatly improved patient prognosis, primary or acquired resistance to anti-HER2 therapy remains a major clinical challenge, leading to treatment failure and disease progression. Recent research has elucidated diverse resistance mechanisms, including HER2 signaling pathway aberrations (such as receptor mutations, alternative splicing, and bypass activation), tumor microenvironment remodeling (involving immunosuppressive cells, metabolic reprogramming, and immune checkpoint molecules), and ADC-specific resistance (impaired internalization, lysosomal dysfunction, payload efflux, and ferroptosis blockade). However, existing reviews primarily focus on trastuzumab and classical signaling pathways, with insufficient integration of ADC-specific mechanisms or microenvironmental immune evasion. Furthermore, the translation of mechanistic discoveries into clinical strategies remains weak, and a systematic summary of validated biomarkers (e.g., PIK3CA mutations, PTEN loss, p95HER2, ADAR1, HLA-G) and related clinical trials is lacking. The purpose of this review is threefold: (1) to systematically integrate recent advances in anti-HER2 resistance mechanisms from three perspectives—HER2 signaling abnormalities, tumor microenvironment remodeling, and ADC-specific barriers; (2) to provide an evidence-based framework for target prioritization by categorizing mechanisms according to their validation stage (clinically validated, substantial in vivo evidence, or in vitro studies only); and (3) to summarize current biomarker-driven clinical trials and emerging therapeutic strategies, including combination immunotherapy, CDK4/6 inhibitors, PI3K PROTACs, and cold atmospheric plasma. Ultimately, this review aims to bridge the gap between basic research and clinical practice, offering practical guidance for overcoming anti-HER2 resistance through precision combination strategies in HER2-positive breast cancer.