biostudies-literatureHamdan FEuropean Research CouncilJane ja Aatos Erkon SäätiöJane ja Aatos Erkon Säätiö (Jane and Aatos Erkko Foundation)1757https://www.ebi.ac.uk/biostudies/studies/S-EPMC12914026biostudies-literatureUnknown17(1)Colorectal cancer (CRC) remains refractory to most immunotherapies, with cancer vaccines failing due to an immunosuppressive tumor microenvironment. Here, we show that β-glucan-induced trained immunity overcomes these barriers by reprogramming macrophages through H3K4me3-dependent epigenetic modifications and metabolic rewiring. In female mice vaccinated with peptide-coated adenovirus-based vaccine PeptiCrad, training enhances glycolysis with creatine metabolism sustaining CXCL9/10 production, enabling macrophages to recruit NK cells via CXCR3. In turn, NK cells produce CCL5, driving cDC1 infiltration and antigen presentation, which together amplify effector memory CD8⁺ T cell responses. Moreover, with human peripheral blood mononuclear cells and CRC patient-derived organoids, trained macrNature communicationsLeveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to enhance colorectal cancer vaccine response.PMC129140264705796681219Hamdan FD'Alessio FGiannoula YNieminen AISakalauskaite MGandolfi SStigzelius VSeppala TTRusso SIzci OCerullo VNapolano AAlanen KMZaghen EAntignani GBottega PFeodoroff MSandberg JZambrano NGronholm MChiaro JMustjoki SFusciello MEriksson OKolikova JfalseLeveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to enhance colorectal cancer vaccine response.Colorectal cancer (CRC) remains refractory to most immunotherapies, with cancer vaccines failing due to an immunosuppressive tumor microenvironment. Here, we show that β-glucan-induced trained immunity overcomes these barriers by reprogramming macrophages through H3K4me3-dependent epigenetic modifications and metabolic rewiring. In female mice vaccinated with peptide-coated adenovirus-based vaccine PeptiCrad, training enhances glycolysis with creatine metabolism sustaining CXCL9/10 production, enabling macrophages to recruit NK cells via CXCR3. In turn, NK cells produce CCL5, driving cDC1 infiltration and antigen presentation, which together amplify effector memory CD8⁺ T cell responses. Moreover, with human peripheral blood mononuclear cells and CRC patient-derived organoids, trained macr2026-01-01T00:00:00Z2026 Jan2026-07-16T06:32:47.155Z2026-07-09T10:39:39.129ZS-EPMC129140264160592010.1038/s41467-026-68466-5