Approximately 20% of breast cancers have amplification of the gene encoding HER2, a protein that promotes cell growth and proliferation. While there are therapies designed specifically to treat HER2-positive cancer, treatment resistance presents a substantial challenge. The Gorski laboratory recently discovered a novel association between HER2 and an autophagy-related cysteine protease called ATG4B and found that ATG4B inhibition sensitizes treatment-resistant HER2-positive breast cancer cell lines to anti-HER2 treatment. As a result, they are investigating the clinical relevance, therapeutic potential, and regulation of ATG4B in the context of HER2-positive breast cancer. Understanding how HER2 influences ATG4B could lead to the identification of new targets or combination targeting strategies. These studies have the potential to validate ATG4B as a new therapeutic target to help overcome treatment resistance in HER2-positive breast cancers.