Effect of repurposed metabolic drugs on human macrophage polarization and antitumoral activity

Ana Vizcaino-Castro; Shipeng Chen; Baukje Nynke Hoogeboom; Annemarie Boerma; Toos Daemen; Cesar Oyarce

doi:10.1016/j.clim.2025.110440

Effect of repurposed metabolic drugs on human macrophage polarization and antitumoral activity

Ana Vizcaino-Castro
, Shipeng Chen
, Baukje Nynke Hoogeboom
, Annemarie Boerma
, Toos Daemen^*
, Cesar Oyarce^*

^*Corresponding author for this work

Microbes in Health and Disease (MHD)

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

2 Citations (Scopus)

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Abstract

AIM: This study aimed to investigate whether the polarization of monocyte-derived macrophages towards an anti-inflammatory phenotype could be hindered by modulating cellular metabolism. Several metabolic drugs were selected: Perhexiline (PerHx) and Nitazoxanide (NTZ) targeting fatty acid oxidation, CB839 (Telaglenastat) targeting glutaminolysis and Metformin (Metf) targeting the mitochondrial electron transport chain.

RESULTS: Our findings demonstrate that the presence of PerHx, NTZ, and CB839 during IL-4-mediated macrophages polarization impaired the acquisition of full anti-inflammatory phenotype, as evidenced by reduced expression of CD163 and CD209 and decreased secretion of CCL17 chemokine. Besides, CB839 induced tumoricidal activity in macrophages, comparable to that observed in macrophages activated by LPS and IFNγ.

CONCLUSION: This study reveals that targeting glutamine metabolism with CB839 effectively blocks the IL-4-induced anti-inflammatory phenotype in macrophages and enhances their tumor-killing capability. Our results provide a compelling rationale for repurposing metabolic drugs to create a pro-inflammatory tumor microenvironment, thereby potentially enhancing the efficacy of current immunotherapies.

Original language	English
Article number	110440
Number of pages	10
Journal	Clinical Immunology
Volume	272
Early online date	29-Jan-2025
DOIs	https://doi.org/10.1016/j.clim.2025.110440
Publication status	Published - Mar-2025

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title = "Effect of repurposed metabolic drugs on human macrophage polarization and antitumoral activity",

abstract = "AIM: This study aimed to investigate whether the polarization of monocyte-derived macrophages towards an anti-inflammatory phenotype could be hindered by modulating cellular metabolism. Several metabolic drugs were selected: Perhexiline (PerHx) and Nitazoxanide (NTZ) targeting fatty acid oxidation, CB839 (Telaglenastat) targeting glutaminolysis and Metformin (Metf) targeting the mitochondrial electron transport chain.RESULTS: Our findings demonstrate that the presence of PerHx, NTZ, and CB839 during IL-4-mediated macrophages polarization impaired the acquisition of full anti-inflammatory phenotype, as evidenced by reduced expression of CD163 and CD209 and decreased secretion of CCL17 chemokine. Besides, CB839 induced tumoricidal activity in macrophages, comparable to that observed in macrophages activated by LPS and IFNγ.CONCLUSION: This study reveals that targeting glutamine metabolism with CB839 effectively blocks the IL-4-induced anti-inflammatory phenotype in macrophages and enhances their tumor-killing capability. Our results provide a compelling rationale for repurposing metabolic drugs to create a pro-inflammatory tumor microenvironment, thereby potentially enhancing the efficacy of current immunotherapies.",

author = "Ana Vizcaino-Castro and Shipeng Chen and Hoogeboom, \{Baukje Nynke\} and Annemarie Boerma and Toos Daemen and Cesar Oyarce",

year = "2025",

month = mar,

doi = "10.1016/j.clim.2025.110440",

language = "English",

volume = "272",

journal = "Clinical Immunology",

issn = "1521-6616",

publisher = "ACADEMIC PRESS INC ELSEVIER SCIENCE",

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TY - JOUR

T1 - Effect of repurposed metabolic drugs on human macrophage polarization and antitumoral activity

AU - Vizcaino-Castro, Ana

AU - Chen, Shipeng

AU - Hoogeboom, Baukje Nynke

AU - Boerma, Annemarie

AU - Daemen, Toos

AU - Oyarce, Cesar

PY - 2025/3

Y1 - 2025/3

N2 - AIM: This study aimed to investigate whether the polarization of monocyte-derived macrophages towards an anti-inflammatory phenotype could be hindered by modulating cellular metabolism. Several metabolic drugs were selected: Perhexiline (PerHx) and Nitazoxanide (NTZ) targeting fatty acid oxidation, CB839 (Telaglenastat) targeting glutaminolysis and Metformin (Metf) targeting the mitochondrial electron transport chain.RESULTS: Our findings demonstrate that the presence of PerHx, NTZ, and CB839 during IL-4-mediated macrophages polarization impaired the acquisition of full anti-inflammatory phenotype, as evidenced by reduced expression of CD163 and CD209 and decreased secretion of CCL17 chemokine. Besides, CB839 induced tumoricidal activity in macrophages, comparable to that observed in macrophages activated by LPS and IFNγ.CONCLUSION: This study reveals that targeting glutamine metabolism with CB839 effectively blocks the IL-4-induced anti-inflammatory phenotype in macrophages and enhances their tumor-killing capability. Our results provide a compelling rationale for repurposing metabolic drugs to create a pro-inflammatory tumor microenvironment, thereby potentially enhancing the efficacy of current immunotherapies.

AB - AIM: This study aimed to investigate whether the polarization of monocyte-derived macrophages towards an anti-inflammatory phenotype could be hindered by modulating cellular metabolism. Several metabolic drugs were selected: Perhexiline (PerHx) and Nitazoxanide (NTZ) targeting fatty acid oxidation, CB839 (Telaglenastat) targeting glutaminolysis and Metformin (Metf) targeting the mitochondrial electron transport chain.RESULTS: Our findings demonstrate that the presence of PerHx, NTZ, and CB839 during IL-4-mediated macrophages polarization impaired the acquisition of full anti-inflammatory phenotype, as evidenced by reduced expression of CD163 and CD209 and decreased secretion of CCL17 chemokine. Besides, CB839 induced tumoricidal activity in macrophages, comparable to that observed in macrophages activated by LPS and IFNγ.CONCLUSION: This study reveals that targeting glutamine metabolism with CB839 effectively blocks the IL-4-induced anti-inflammatory phenotype in macrophages and enhances their tumor-killing capability. Our results provide a compelling rationale for repurposing metabolic drugs to create a pro-inflammatory tumor microenvironment, thereby potentially enhancing the efficacy of current immunotherapies.

U2 - 10.1016/j.clim.2025.110440

DO - 10.1016/j.clim.2025.110440

M3 - Article

C2 - 39889896

SN - 1521-6616

VL - 272

JO - Clinical Immunology

JF - Clinical Immunology

M1 - 110440

ER -

Effect of repurposed metabolic drugs on human macrophage polarization and antitumoral activity

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