{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T05:27:36Z","timestamp":1787290056625,"version":"build-2736575974"},"reference-count":32,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003661","name":"Korea Institute for Advancement of Technology","doi-asserted-by":"publisher","award":["RS2024\u201000424744"],"award-info":[{"award-number":["RS2024\u201000424744"]}],"id":[{"id":"10.13039\/501100003661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Tumor\u2010associated macrophages (TAMs), particularly the M2\u2010like subtype, contribute to an immunosuppressive tumor microenvironment and promote tumor progression. Melittin, a natural bioactive peptide derived from bee venom, has been reported to exert anticancer and immunomodulatory effects; however, the cellular targets and molecular mechanisms underlying its selective action on TAMs remain incompletely defined. This study aimed to investigate the immunomodulatory effects of melittin on TAM subsets and to identify the molecular determinant responsible for its selectivity toward M2\u2010like macrophages. Macrophage subsets were analyzed following melittin treatment using flow cytometry, gene expression analysis, and immunofluorescence. Binding interactions were assessed by biochemical and biophysical approaches. Tumor growth and immune cell composition were examined in wild\u2010type and CD18\u2010deficient mice. Melittin treatment selectively reduced M2\u2010like TAM populations while increasing infiltration of CD8\n                    <jats:sup>+<\/jats:sup>\n                    cytotoxic T cells in tumor tissues. Mechanistic analyses revealed that melittin preferentially binds to the integrin subunit CD18 (ITGB2), which is enriched in M2\u2010polarized macrophages, leading to disruption of M2\u2010associated phenotypes in\u00a0vitro. Notably, genetic deletion of CD18 abolished the M2\u2010suppressive and antitumor effects of melittin in\u00a0vivo. These findings demonstrate that CD18 is functionally required for the immunomodulatory and antitumor activities of native full\u2010length melittin. This study provides mechanistic insight into the selective action of a natural bioactive peptide and supports its potential as a lead compound for natural product\u2010based immunomodulatory strategies.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70431","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T05:16:35Z","timestamp":1787289395000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Melittin Reprograms Tumor\u2010Associated Macrophages Through\n                    <scp>CD18<\/scp>\n                    \u2010Mediated Immunomodulation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8145-6645","authenticated-orcid":false,"given":"Ik\u2010Hwan","family":"Han","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Korean Medicine Kyung Hee University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7948-6624","authenticated-orcid":false,"given":"Hyunju","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Korean Medicine Kyung Hee University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7807-5620","authenticated-orcid":false,"given":"Eunbin","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Clinical Korean Medicine, Graduate School Kyung Hee University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9698-0899","authenticated-orcid":false,"given":"Ilseob","family":"Choi","sequence":"additional","affiliation":[{"name":"Twinpig Biolab Inc. R&amp;D Center  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2273-0931","authenticated-orcid":false,"given":"Soyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Twinpig Biolab Inc. R&amp;D Center  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deok\u2010Sang","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Clinical Korean Medicine, Graduate School Kyung Hee University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0299-3582","authenticated-orcid":false,"given":"Hyunsu","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Korean Medicine Kyung Hee University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1182\/blood.V75.5.1037.1037","article-title":"Structure and Function of the Leukocyte Adhesion Molecules CD11\/CD18","volume":"75","author":"Arnaout M. 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I.","year":"2010","journal-title":"Cell"},{"key":"e_1_2_12_13_1","doi-asserted-by":"crossref","first-page":"e011422","DOI":"10.1136\/jitc-2024-011422","article-title":"Conformation\u2010Sensitive Targeting of CD18 Depletes M2\u2010Like Tumor\u2010Associated Macrophages Resulting in Inhibition of Solid Tumor Progression","volume":"13","author":"Han I. 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Drug Discovery"},{"key":"e_1_2_12_20_1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.coi.2010.01.009","article-title":"Macrophages, Innate Immunity and Cancer: Balance, Tolerance, and Diversity","volume":"22","author":"Mantovani A.","year":"2010","journal-title":"Current Opinion in Immunology"},{"key":"e_1_2_12_21_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.immuni.2014.06.010","article-title":"Tumor\u2010Associated Macrophages: From Mechanisms to Therapy","volume":"41","author":"Noy R.","year":"2014","journal-title":"Immunity"},{"key":"e_1_2_12_22_1","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/0091-6749(77)90056-2","article-title":"Melittin: An Allergen of Honeybee Venom","volume":"59","author":"Paull B. 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