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Here, we investigated the role of the cannabinoid CB\n                    <jats:sub>2<\/jats:sub>\n                    receptor (CB\n                    <jats:sub>2<\/jats:sub>\n                    R) in trastuzumab resistance. In human breast cancer samples, a decreased expression of HER2-CB\n                    <jats:sub>2<\/jats:sub>\n                    R heterodimers following neoadjuvant treatment, due to CB\n                    <jats:sub>2<\/jats:sub>\n                    R downregulation, was linked to poor long-term outcomes. Using various preclinical models, we demonstrate that CB\n                    <jats:sub>2<\/jats:sub>\n                    R drives trastuzumab resistance. Mechanistically, CB\n                    <jats:sub>2<\/jats:sub>\n                    R loss enabled cancer cells to evade antitumor IFN-\u03b3 signaling while promoting a shift from HER2-CB\n                    <jats:sub>2<\/jats:sub>\n                    R to HER2-EGFR heterodimers, thus reducing dependence on HER2 and increasing reliance on EGFR-mediated pathways. Moreover, EGFR inhibition restored trastuzumab sensitivity. In summary, we reveal an unprecedented role for CB\n                    <jats:sub>2<\/jats:sub>\n                    R as a key regulator of oncogenic and immune signaling in response to anti-HER2 therapy and its potential as a predictive biomarker of therapeutic efficacy. We also propose dual HER2\/EGFR targeting and non-CB\n                    <jats:sub>2<\/jats:sub>\n                    R-selective cannabinoid therapies as potential strategies to overcome CB\n                    <jats:sub>2<\/jats:sub>\n                    R-mediated trastuzumab resistance. Together, these findings position the endocannabinoid system as a pivotal and actionable node to elucidate, anticipate, and counteract resistance to HER2-targeted therapies.\n                  <\/jats:p>","DOI":"10.1038\/s41388-026-03814-9","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T11:09:21Z","timestamp":1778497761000},"page":"2436-2451","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cannabinoid CB2 receptor drives trastuzumab resistance and predicts durable anti-HER2 response"],"prefix":"10.1038","volume":"45","author":[{"given":"Marta","family":"Seijo-Vila","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sof\u00eda 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