Abstract
Despite advances in HER2-targeted therapies and CSC-directed agents, resistance remains a major barrier in breast cancer. Synthesize evidence for exercise as a precision strategy to disrupt HER2/CD44-driven resistance circuits. Preclinical and clinical data demonstrate that physical activity: (1) downregulates HER2/PI3K signaling via myokine-mediated pathways (IL-6/SPARC), (2) reduces CD44 through NK-dependent immune surveillance, and (3) synergizes with biologics to overcome cardiotoxicity and chemoresistance. Molecular subtype-specific exercise prescriptions are defined. Exercise reprograms the tumor-immune microenvironment to target therapy-resistant pathways, establishing a paradigm for exercise as adjuvant precision medicine.