Melittin Reprograms Tumor‐Associated Macrophages Through CD18 ‐Mediated Immunomodulation

ABSTRACT Tumor‐associated macrophages (TAMs), particularly the M2‐like 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‐like 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‐type and CD18‐deficient mice. Melittin treatment selectively reduced M2‐like TAM populations while increasing infiltration of CD8 + cytotoxic T cells in tumor tissues. Mechanistic analyses revealed that melittin preferentially binds to the integrin subunit CD18 (ITGB2), which is enriched in M2‐polarized macrophages, leading to disruption of M2‐associated phenotypes in vitro. Notably, genetic deletion of CD18 abolished the M2‐suppressive and antitumor effects of melittin in vivo. These findings demonstrate that CD18 is functionally required for the immunomodulatory and antitumor activities of native full‐length 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‐based immunomodulatory strategies.