There is a subtype of breast cancer characterized by the overexpression of the oncogene HER2. Although most patients with this diagnosis benefit from HER2-targeted treatments, some do not respond to these therapies and others develop resistance with time. New tools are therefore warranted for the treatment of this patient population, and for early identification of those individuals at a higher risk of developing innate or acquired resistance to current treatments. Here, we show that HER2 forms heteromer complexes with the cannabinoid receptor CB2R, the expression of these structures correlates with poor patient prognosis, and their disruption promotes antitumor responses. Collectively, our results support HER2–CB2R heteromers as new therapeutic targets and prognostic tools in HER2+ breast cancer.