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

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

doi:10.1038/s41467-026-68466-5

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

7 Citations (Scopus)

9 Downloads (Pure)

Abstract

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.

Original language	English
Article number	1757
Journal	Nature Communications
Volume	17
Issue number	1
DOIs	https://doi.org/10.1038/s41467-026-68466-5
Publication status	Published - Feb 2026
Publication type	A1 Journal article-refereed

Funding

The flow cytometry analysis was performed at the HiLife Flow Cytometry Unit, University of Helsinki. We acknowledge the Helsinki Metabolomics Center, supported by HiIFE and Biocenter Finland. The single-cell RNA sequencing was performed with FIMM Single-Cell Analytics and Sequencing units supported by HiLIFE and Biocenter Finland. We are also grateful for Dr. Cristian Smerdou (Cima Universidad de Navarra) for kindly gifting us the MC38 cell line. We would also like to acknowledge bachelor student, Karim Hamdan, for helping in some experiments. This work has been supported by European Research Council (ERC), Horizon 2020 (H2020) framework (Agreement No. 681219) (V.C.), Magnus Ehrnrooth Foundation (project No. 4706235) (V.C.), Jane and Aatos Erkko Foundation (Project No. 4705796) (V.C.), Finnish Cancer Foundation (project No. 4706116) (V.C.), Helsinki Institute of Life Science (HiLIFE) (project No. 797011004) (V.C.), Digital Precision Cancer Medicine Flagship iCAN (V.C.), GeneCellNano flagship (V.C.), HiLIFE HiPOC (FH), Research Council of Finland (TTS) and iCAN Digital Precision Cancer Medicine Flagship (TTS), and research grants by Jane and Aatos Erkko Foundation (TTS), Sigrid Juselius Foundation (TTS), Mary and Georg Ehrnrooth Foundation (TTS), Cancer Foundation Finland (TTS), Relander Foundation (TTS), and HUS(TTS) and Pirha state research funding (TTS).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Publication forum classification

Publication forum level 3

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-026-68466-5Licence: CC BY-NC-ND

Leveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to enhance colorectal cancer vaccine responseFinal published version, 4.37 MBLicence: CC BY-NC-ND

https://urn.fi/URN:NBN:fi:tuni-202603063007Licence: CC BY-NC-ND

Cite this

Hamdan, F., Gandolfi, S., D’Alessio, F., Giannoula, Y., Kolikova, J., Fusciello, M., Zaghen, E., Napolano, A., Russo, S., Izci, O., Bottega, P., Chiaro, J., Alanen, K. M., Antignani, G., Feodoroff, M., Stigzelius, V., Sakalauskaite, M., Sandberg, J., Nieminen, A. I., ... Cerullo, V. (2026). Leveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to enhance colorectal cancer vaccine response. Nature Communications, 17(1), Article 1757. https://doi.org/10.1038/s41467-026-68466-5

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abstract = "Colorectal cancer (CRC) remains refractory to most immunotherapies, with cancer vaccines failing due to an immunosuppressive tumor microenvironment. Here, we show that β-glucan{\textendash}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.",

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Hamdan, F, Gandolfi, S, D’Alessio, F, Giannoula, Y, Kolikova, J, Fusciello, M, Zaghen, E, Napolano, A, Russo, S, Izci, O, Bottega, P, Chiaro, J, Alanen, KM, Antignani, G, Feodoroff, M, Stigzelius, V, Sakalauskaite, M, Sandberg, J, Nieminen, AI, Zambrano, N, Eriksson, O, Mustjoki, S, Seppälä, TT, Grönholm, M & Cerullo, V 2026, 'Leveraging glucan-induced trained immunity for the epigenetic and metabolic rewiring of macrophages to enhance colorectal cancer vaccine response', Nature Communications, vol. 17, no. 1, 1757. https://doi.org/10.1038/s41467-026-68466-5

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AU - Hamdan, Firas

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AU - D’Alessio, Federica

AU - Giannoula, Yvonne

AU - Kolikova, Julia

AU - Fusciello, Manlio

AU - Zaghen, Elisa

AU - Napolano, Alessandra

AU - Russo, Salvatore

AU - Izci, Ozan

AU - Bottega, Paolo

AU - Chiaro, Jacopo

AU - Alanen, Kirsi Marja

AU - Antignani, Gabriella

AU - Feodoroff, Michaela

AU - Stigzelius, Virpi

AU - Sakalauskaite, Milda

AU - Sandberg, Janita

AU - Nieminen, Anni I.

AU - Zambrano, Nicola

AU - Eriksson, Ove

AU - Mustjoki, Satu

AU - Seppälä, Toni T.

AU - Grönholm, Mikaela

AU - Cerullo, Vincenzo

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AB - 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.

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DO - 10.1038/s41467-026-68466-5

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AN - SCOPUS:105030395483

SN - 2041-1723

VL - 17

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1757

ER -

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

Abstract

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