Abstract: Breast cancer is not a single disease but a group of distinct subtypes, each with its own molecular and clinical characteristics. Elevated levels of a protein known as HER2 on tumor cells define a molecular subtype that makes up about 15-20% of all breast cancer cases. This HER2-positive (HER2+) breast cancer subtype is aggressive and carries a poor prognosis due to the rapid growth and division of the tumor cells, their ability to survive and resist drugs, and their strong tendency to metastasize. Considerable effort has been invested in the development of drugs that block the activity of the HER2 protein, with several FDA-approved options now available. This has prolonged survival for a much larger proportion of HER2+ breast cancer patients than in the past. Many of these patients are not cured, however, and HER2+ disease is still considered to be one of the most aggressive, poor-outcome subtypes of breast cancer. Based on these observations, new ways of treating HER2+ breast cancer are needed to eradicate this disease. Recently developed treatments have revolutionized cancer therapy by harnessing the power of the immune system to attack and destroy tumors. Known as “immunotherapies,” these drugs can stop the growth and progression of some cancers and even produce cures for some patients with specific types of cancer. A class of immunotherapy known as “adoptive cell therapy” uses immune cells genetically engineered to have anti-cancer properties. To accelerate the development of these therapies and deliver benefits to breast cancer patients more quickly, this collaboration established a new method to improve our understanding of the genetic elements controlling anti-cancer functions of primary immune cells. A unique droplet microfluidics based genetic engineering technology from the commercial partner was coupled with expertise in HER2 breast cancer of the academic partner to facilitate the discovery of targets to improve therapeutic performance. The platform enables the rapid and cost effective generation of large numbers of targeted modifications in the genomes of precious primary immune cells genetically engineered to target HER2. Engineered cell lines can then be tested for interactions with tumor cells in patient derived HER2 breast cancer samples and communication with other cell types to organize an immune response against the tumor was evaluated. We anticipate that this platform will help generate breakthrough therapies by creating high dimensional data sets from genetic screens in individual patients, providing effective new options for patients with aggressive and hard-to-treat breast cancers.