135 HER2-positive breast cancer, a particularly aggressive subtype, accounts for approximately 15% of all breast cancer cases worldwide. While significant strides have been made in targeted therapies, such as trastuzumab and antibody-drug conjugates, resistance remains a persistent hurdle in achieving optimal outcomes for many patients. The findings were published in the journal Critical Reviews in Oncology/Hematology. Researchers have pinpointed tumour heterogeneity as a key challenge in treating HER2-positive breast cancer. This variability in HER2 expression across tumours and over time complicates diagnosis and treatment, often leading to reduced efficacy of therapies. Moreover, current diagnostic methods, including immunohistochemistry, exhibit inconsistencies, underscoring the need for standardised testing to improve accuracy and treatment decisions. Antibody-binding effectiveness is another critical factor influencing treatment outcomes. Truncated HER2 protein fragments, such as p95HER2, and glycoproteins like MUC4 can hinder antibody therapies by masking binding sites. This results in diminished therapeutic efficacy, leaving some patients unresponsive to standard treatments. The tumour microenvironment plays a pivotal role in resistance development. Cancer-associated fibroblasts and altered immune responses within the tumour site often promote drug resistance. These changes can weaken immune-mediated tumour destruction, enabling cancer cells to survive and proliferate. Additionally, tumour reliance on fatty acid metabolism and glycolysis has been linked to resistance, suggesting potential metabolic vulnerabilities that could be exploited therapeutically. Aberrant signalling pathways, such as the PI3K/Akt/mTOR axis, frequently contribute to resistance. Mutations in PIK3CA or loss of the PTEN gene can lead to unchecked tumour growth and reduced responsiveness to targeted therapies. Blocking these pathways with specific inhibitors has shown promise in overcoming resistance in clinical trials. To address these challenges, researchers are exploring innovative approaches, including more precise HER2 detection methods, predictive modelling, and combination therapies. For instance, incorporating artificial intelligence into diagnostic processes could enhance accuracy, while the HER2DX genomic test offers a promising tool for predicting treatment response. Immunotherapy and metabolic interventions are also emerging as potential strategies. By targeting tumour-specific metabolic pathways or bolstering immune responses, researchers aim to improve outcomes for patients who experience resistance to current therapies. Despite these efforts, the path to overcoming resistance in HER2-positive breast cancer remains complex. Continued research and collaboration will be essential in developing novel strategies to enhance treatment efficacy and improve survival rates.