Recent advances in HER2-targeted inhibitors for cancer therapy.

HER2 (ErbB2), a ligand-independent HER family member, regulates cell growth, differentiation, and survival. Its overexpression, gene amplification, and activating mutations are oncogenic drivers in multiple malignancies. The past two decades have witnessed transformative advances in HER2-targeted therapeutics, exemplified by tyrosine kinase inhibitors (TKIs), including first-generation reversible pan-HER (e.g., lapatinib), second-generation covalent pan-HER (neratinib, pyrotinib), and novel selective HER2 inhibitors (tucatinib, sevabertinib, zongertinib). Nonetheless, the extensive molecular heterogeneity in HER2 activation (e.g., dimerization, amplification) and mutation profiles (e.g., L755S, exon 20 insertions), combined with tumor-type-specific pathogenic mechanisms, poses significant challenges to precision oncology in clinical practice. Currently, numerous promising inhibitors in preclinical and clinical development hold potential for providing more effective treatment options. This review comprehensively summarizes recent advances in HER2-targeted TKIs and their emergent resistance mechanisms, further analyzing strategies to both mitigate off-target toxicity and overcome resistance through rational design of selective HER2 inhibitors. Collectively, these insights provide a roadmap for developing next-generation precision therapies in HER2-driven cancers.