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<p>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 macrophages boost NK migration, antigen-specific T cell activation, and tumor killing. These findings highlight trained immunity as a powerful adjuvant to reinvigorate colorectal cancer vaccination.</p>

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Leveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to enhance colorectal cancer vaccine response

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月28日

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  • Firas Hamdan,
  • Sara Gandolfi,
  • Federica D’Alessio,
  • Yvonne Giannoula,
  • Julia Kolikova,
  • Manlio Fusciello,
  • Elisa Zaghen,
  • Alessandra Napolano,
  • Salvatore Russo,
  • Ozan Izci,
  • Paolo Bottega,
  • Jacopo Chiaro,
  • Kirsi-Marja Alanen,
  • Gabriella Antignani,
  • Michaela Feodoroff,
  • Virpi Stigzelius,
  • Milda Sakalauskaite,
  • Janita Sandberg,
  • Anni I. Nieminen,
  • Nicola Zambrano,
  • Ove Eriksson,
  • Satu Mustjoki,
  • Toni T. Seppälä,
  • Mikaela Grönholm,
  • Vincenzo Cerullo

摘要

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 macrophages boost NK migration, antigen-specific T cell activation, and tumor killing. These findings highlight trained immunity as a powerful adjuvant to reinvigorate colorectal cancer vaccination.