{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T02:46:13Z","timestamp":1789267573796,"version":"build-2803163510"},"reference-count":100,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gastric cancer (GC) remains a major cause of cancer-related mortality worldwide, with human epidermal growth factor receptor 2 (HER2)-positive disease representing a clinically relevant subset. Trastuzumab combined with chemotherapy is the standard first-line treatment in advanced settings, following the landmark ToGA trial. However, resistance to trastuzumab has emerged as a significant limitation, prompting the need for more effective second-line therapies. Trastuzumab deruxtecan, a novel antibody\u2013drug conjugate (ADC) composed of trastuzumab linked to a cytotoxic payload, has demonstrated promising efficacy in trastuzumab-refractory, HER2-positive GC, including cases with heterogeneous HER2 expression. Other HER2-targeted ADCs are also under investigation as potential alternatives. In addition, strategies to overcome resistance include HER2-specific immune-based therapies, such as peptide vaccines and chimeric antigen receptor T cell therapies, as well as antibodies targeting distinct HER2 domains or downstream signaling pathways like PI3K\/AKT. These emerging approaches aim to improve efficacy in both HER2-high and HER2-low GC. As HER2-targeted treatments evolve, addressing resistance mechanisms and optimizing therapy for broader patient populations is critical. This review discusses current and emerging HER2-directed strategies in GC, focusing on trastuzumab deruxtecan and beyond, and outlines future directions to improve outcomes for patients with HER2-positive GC across all clinical settings.<\/jats:p>","DOI":"10.3390\/ijms26157285","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T10:51:14Z","timestamp":1753699874000},"page":"7285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Fighting HER2 in Gastric Cancer: Current Approaches and Future Landscapes"],"prefix":"10.3390","volume":"26","author":[{"given":"Margherita","family":"Ratti","sequence":"first","affiliation":[{"name":"Oncology and Hematology Department, Piacenza General Hospital, Via Taverna 49, 29121 Piacenza, PC, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2119-775X","authenticated-orcid":false,"given":"Chiara","family":"Citterio","sequence":"additional","affiliation":[{"name":"Oncology and Hematology Department, Piacenza General Hospital, Via Taverna 49, 29121 Piacenza, PC, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2559-7558","authenticated-orcid":false,"given":"Elena","family":"Orlandi","sequence":"additional","affiliation":[{"name":"Oncology and Hematology Department, Piacenza General Hospital, Via Taverna 49, 29121 Piacenza, PC, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0578-0870","authenticated-orcid":false,"given":"Stefano","family":"Vecchia","sequence":"additional","affiliation":[{"name":"Pharmacy Unit, Piacenza General Hospital, Via Taverna 49, 29121 Piacenza, PC, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Anselmi","sequence":"additional","affiliation":[{"name":"Oncology and Hematology Department, Piacenza General Hospital, Via Taverna 49, 29121 Piacenza, PC, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5217-3859","authenticated-orcid":false,"given":"Ilaria","family":"Toscani","sequence":"additional","affiliation":[{"name":"Oncology and Hematology Department, Piacenza General Hospital, Via Taverna 49, 29121 Piacenza, PC, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Rotolo","sequence":"additional","affiliation":[{"name":"School of Medical Oncology, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41124 Modena, MO, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Salati","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, University Hospital of Modena, 41124 Modena, MO, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5435-1218","authenticated-orcid":false,"given":"Michele","family":"Ghidini","sequence":"additional","affiliation":[{"name":"Oncology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, MI, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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