HER2 in solid tumors: microenvironment features and multifaceted advances from mechanisms to clinical translation

Human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver in multiple solid tumors, most prominently in breast and gastric cancers. Beyond gene amplification–driven signaling through canonical PI3K/AKT and RAS/MAPK pathways, emerging evidence reveals that HER2 functions within a highly dynamic and context-dependent tumor ecosystem. Interactions between HER2-positive tumor cells and immune and stromal compartments actively shape the tumor microenvironment, contributing to immune evasion, therapeutic resistance and disease progression. A central challenge in the clinical management of HER2-altered cancers is pronounced spatial and temporal heterogeneity, which undermines both diagnostic accuracy and the durability of targeted therapies. In response, advances in multi-omics profiling, liquid biopsy technologies and artificial intelligence–assisted analytics are redefining HER2 assessment, shifting it from static tissue-based classification towards dynamic, minimally invasive monitoring. In parallel, the therapeutic landscape has evolved from single-agent HER2 blockade to rational combination strategies. In particular, antibody–drug conjugates have emerged as a transformative modality, extending the therapeutic reach of HER2 targeting beyond traditional indications and offering new opportunities to overcome heterogeneity and drug resistance. This review synthesizes current insights into the molecular and microenvironmental biology of HER2-altered solid tumors and discusses how these advances are reshaping next-generation precision oncology.