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Paclitaxel (PTX) is commonly used, but resistance often arises, highlighting the need for targeted therapies. Cannabinoid receptor type 2 (CB2R) is overexpressed in several cancers and its activation has been associated with reduced tumor growth and metastasis. This study evaluated the antitumor activity of selected CB2R agonists with dual activity (<jats:bold>CC48<\/jats:bold> and <jats:bold>Fi9<\/jats:bold>) compared to single-target compounds (<jats:bold>ASF151<\/jats:bold>), a reference agonist (<jats:bold>compound 1<\/jats:bold>), and an antagonist (<jats:bold>AM630<\/jats:bold>). The compounds\u2019 cytotoxicity was determined in GC lines, including PTX-resistant cells, with different levels of CB2R expression. Firstly, were ported that the addition of CB2R ligands to PTX significantly reduces the actively proliferating cells (Ki67+) even in chemotherapy-resistant GC cells. Concentrations below the IC50 of all compounds were used to minimise toxicity. Activation of Akt\/mTORC1 and MAPK cascades were found to be related to antiproliferative activity, which was found to be independent of CB2R expression in the different cell lines. Surprisingly, both agonist and antagonist compounds inhibited cell growth. The interaction of <jats:bold>CC48<\/jats:bold> and the reference compounds <jats:bold>1<\/jats:bold> and <jats:bold>AM630<\/jats:bold>, with P-glycoprotein (P-gp) could explain their greater effectiveness in overcoming PTX resistance. Furthermore, <jats:bold>CC48<\/jats:bold> was particularly effective among the agonists in inducing the expression of key autophagy proteins and activating the apoptotic pathway via caspase 3\/7 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). The combination of <jats:bold>CC48<\/jats:bold> with PTX further amplified this effect in both sensitive and resistant cells (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). <jats:bold>CC48<\/jats:bold> significantly reduced GC cells migration and epithelial-mesenchymal transition (EMT) by modulating the vimentin protein (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). In an orthotopic mouse model, <jats:bold>CC48<\/jats:bold> inhibits tumor volume (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01)and also reduces the number of Ki67\u2009+\u2009cells (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), without cytotoxic effects. Histological analysis revealed widespread necrosis with inflammatory and apoptotic features, including pyknotic nuclei and fibrotic replacement in <jats:bold>CC48-<\/jats:bold>treatedtumors. Moreover, <jats:bold>CC48<\/jats:bold> treatment reduced circulating levels of G-CSF, IL-12 (p40), and eotaxin (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), suggesting an immunomodulatory role. In conclusion <jats:bold>CC48<\/jats:bold>, a novel multi-target ligand (MTDL), activating CB2R and inhibiting Fatty Acid Amide Hydrolase (FAAH), effectively blocks GC progression modulating the immune response and overcoming PTX resistance.<\/jats:p>","DOI":"10.1186\/s13046-025-03476-7","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T02:37:37Z","timestamp":1752633457000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CC48 a new CB2R agonist\/FAAH inhibitor dual drug blocks gastric cancer progression and overcomes paclitaxel resistance"],"prefix":"10.1186","volume":"44","author":[{"given":"Annalisa","family":"Schirizzi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Renna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giampiero","family":"De Leonardis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosangela","family":"Montanaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Mastropasqua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Graziano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Riganti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Pisano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Laghezza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Abate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Stefanachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola Antonio","family":"Colabufo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Caccioppoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giusy","family":"Bianco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Valentini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Armentano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"Giannelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marialessandra","family":"Contino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalba","family":"D\u2019Alessandro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"issue":"3","key":"3476_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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