Modulating the microbiome as an approach to anticancer drug development

Jemma Arakelyan; Ho-Jung Choe; Chengnan Wu; Daniil A. Rusanov; Elena E. Bardina; Anna A. Kirsanova; Yuliya V. Zakalyukina; Nikita Y. Shmelev; Anton P. Tyurin; Vladislav Y. Komarov; Vladimir Kushnarev; Nikolay S. Karnaukhov; Gerald D’Cruz; Eugene S. Vasilyev; Eunice Dotse; Kwan T. Chow; William C. Cho; Alexey V. Tkachev; Artem L. Gushchin; Maria V. Babak

doi:10.1073/pnas.2417269122

Modulating the microbiome as an approach to anticancer drug development

Jemma Arakelyan (Co-first Author)
, Ho-Jung Choe (Co-first Author)
, Chengnan Wu (Co-first Author)
, Daniil A. Rusanov (Co-first Author)
, Elena E. Bardina
, Anna A. Kirsanova
, Yuliya V. Zakalyukina
, Nikita Y. Shmelev
, Anton P. Tyurin
, Vladislav Y. Komarov
, Vladimir Kushnarev
, Nikolay S. Karnaukhov
, Gerald D’Cruz
, Eugene S. Vasilyev
, Eunice Dotse
, Kwan T. Chow
, William C. Cho
, Alexey V. Tkachev
, Artem L. Gushchin^*
, Maria V. Babak^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

3 Citations (Scopus)

1 Downloads (CityUHK Scholars)

Abstract

Recent studies have suggested that the commensal microbiome positively affects cancer prognosis and treatment outcomes. However, only a few strategies for regulating the microbiome composition have been reported. In this study, we identified gold(I) complexes that selectively inhibited nonbeneficial bacterial strains in vitro without affecting commensal Lactobacillus strains. In contrast, clinically used drugs demonstrated comparable effects on both commensal and noncommensal strains. Consistent with the in vitro results, the selected gold(I) complex induced favorable changes in the intratumoral and gastrointestinal microbiomes in vivo. Furthermore, its anticancer efficacy was found to be dependent on the composition of microbiome and correlated with the production of short-chain fatty acid bacterial metabolites. Structure–activity relationship studies have dissected the contribution of each structural component in both the in vivo efficacy and microbiome-modulating properties. Transcriptomic analysis of tumors revealed microbiome-associated gene signaling pathways. These findings provide valuable insights for future research on microbiome-modulating anticancer drugs, presenting potential avenues to optimize cancer treatment outcomes and mitigate side effects such as gastrointestinal dysbiosis. Furthermore, our study provides insights into the involvement of microbiome in the mechanism of action of metal-based chemotherapeutics.

© 2025 the Author(s)

Original language	English
Article number	e2417269122
Number of pages	12
Journal	Proceedings of the National Academy of Sciences
Volume	122
Issue number	44
DOIs	https://doi.org/10.1073/pnas.2417269122
Publication status	Published - 28 Oct 2025

Funding

M.V.B. acknowledges the financial support from the Pneumoconiosis Compensation Fund Board of Hong Kong (Project No. 9211315). A.L.G. acknowledges the financial support from the Russian Science Foundation (grant no. 21-13-00092) and from the Ministry of Science and Higher Education of the Russian Federation (grants N 121031700315-2 and 121031700313-8) for the access to the equipment of the Centre of Collective Usage of NIIC SB RAS. A.V.T. acknowledges the financial support from the Russian Science Foundation (project number 23-73-10157). K.T.C. acknowledges the financial support from the Croucher Foundation (Ref. No. 9509002 and 9500032), The Science and Technology Innovation Committee of Shenzhen Municipality (Ref. No. JCYJ20210324133813036), Hong Kong Research Grants Council (Ref. No. C7008-22G and 11103523), the Tung Biomedical Sciences Centre (Ref. No. 9609306), and City University of Hong Kong (Ref. No. 7005313, 7005518, 7005740, and 7005873).

UN SDGs

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

SDG 3 Good Health and Well-being

Research Keywords

bioinorganic
gold complex
anticancer therapeutic
microbiome
tumor microenvironment

Publisher's Copyright Statement

COPYRIGHT TERMS OF DEPOSITED FINAL PUBLISHED VERSION FILE: This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

RGC Funding Information

RGC-funded

Access Output

10.1073/pnas.2417269122

346912317.pdfFinal Published version, 4.81 MBLicence: CC BY-NC-ND

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2 Finished
5 Active

GRF: Understanding the Myeloid-specific IRF5-mediated Immune Response in Breast Cancer
CHOW, K. T. (Principal Investigator / Project Coordinator), CHAN, K. H. K. (Co-Investigator) & CHIN, R. Y. M. (Co-Investigator)
1/01/24 → …
Project: Research
CRF-ExtU-Lead: The Immune Microenvironment of Recurrent Hepatocellular Carcinoma
WONG, C. L. C. (Main Project Coordinator [External]) & CHOW, K. T. (Principal Investigator / Project Coordinator)
1/06/23 → …
Project: Research
HKgovt: Investigation of Gold Drug Candidates as Immunomodulating Agents for the Treatment of Malignant Pleural Mesothelioma
BABAK, M. (Principal Investigator / Project Coordinator)
1/04/22 → …
Project: Research

Cite this

Arakelyan, J., Choe, H.-J., Wu, C., Rusanov, D. A., Bardina, E. E., Kirsanova, A. A., Zakalyukina, Y. V., Shmelev, N. Y., Tyurin, A. P., Komarov, V. Y., Kushnarev, V., Karnaukhov, N. S., D’Cruz, G., Vasilyev, E. S., Dotse, E., Chow, K. T., Cho, W. C., Tkachev, A. V., Gushchin, A. L., & Babak, M. V. (2025). Modulating the microbiome as an approach to anticancer drug development. Proceedings of the National Academy of Sciences, 122(44), Article e2417269122. https://doi.org/10.1073/pnas.2417269122

@article{a764e0839cf74148b94a9fe4002558c3,

title = "Modulating the microbiome as an approach to anticancer drug development",

abstract = "Recent studies have suggested that the commensal microbiome positively affects cancer prognosis and treatment outcomes. However, only a few strategies for regulating the microbiome composition have been reported. In this study, we identified gold(I) complexes that selectively inhibited nonbeneficial bacterial strains in vitro without affecting commensal Lactobacillus strains. In contrast, clinically used drugs demonstrated comparable effects on both commensal and noncommensal strains. Consistent with the in vitro results, the selected gold(I) complex induced favorable changes in the intratumoral and gastrointestinal microbiomes in vivo. Furthermore, its anticancer efficacy was found to be dependent on the composition of microbiome and correlated with the production of short-chain fatty acid bacterial metabolites. Structure–activity relationship studies have dissected the contribution of each structural component in both the in vivo efficacy and microbiome-modulating properties. Transcriptomic analysis of tumors revealed microbiome-associated gene signaling pathways. These findings provide valuable insights for future research on microbiome-modulating anticancer drugs, presenting potential avenues to optimize cancer treatment outcomes and mitigate side effects such as gastrointestinal dysbiosis. Furthermore, our study provides insights into the involvement of microbiome in the mechanism of action of metal-based chemotherapeutics. {\textcopyright} 2025 the Author(s)",

keywords = "bioinorganic, gold complex, anticancer therapeutic, microbiome, tumor microenvironment",

author = "Jemma Arakelyan and Ho-Jung Choe and Chengnan Wu and Rusanov, \{Daniil A.\} and Bardina, \{Elena E.\} and Kirsanova, \{Anna A.\} and Zakalyukina, \{Yuliya V.\} and Shmelev, \{Nikita Y.\} and Tyurin, \{Anton P.\} and Komarov, \{Vladislav Y.\} and Vladimir Kushnarev and Karnaukhov, \{Nikolay S.\} and Gerald D{\textquoteright}Cruz and Vasilyev, \{Eugene S.\} and Eunice Dotse and Chow, \{Kwan T.\} and Cho, \{William C.\} and Tkachev, \{Alexey V.\} and Gushchin, \{Artem L.\} and Babak, \{Maria V.\}",

year = "2025",

month = oct,

day = "28",

doi = "10.1073/pnas.2417269122",

language = "English",

volume = "122",

journal = "Proceedings of the National Academy of Sciences",

issn = "0027-8424",

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Arakelyan, J, Choe, H-J, Wu, C , Rusanov, DA, Bardina, EE, Kirsanova, AA, Zakalyukina, YV, Shmelev, NY, Tyurin, AP, Komarov, VY, Kushnarev, V, Karnaukhov, NS, D’Cruz, G, Vasilyev, ES, Dotse, E , Chow, KT, Cho, WC, Tkachev, AV, Gushchin, AL & Babak, MV 2025, 'Modulating the microbiome as an approach to anticancer drug development', Proceedings of the National Academy of Sciences, vol. 122, no. 44, e2417269122. https://doi.org/10.1073/pnas.2417269122

Modulating the microbiome as an approach to anticancer drug development. / Arakelyan, Jemma (Co-first Author); Choe, Ho-Jung (Co-first Author); Wu, Chengnan (Co-first Author) et al.
In: Proceedings of the National Academy of Sciences, Vol. 122, No. 44, e2417269122, 28.10.2025.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Modulating the microbiome as an approach to anticancer drug development

AU - Arakelyan, Jemma

AU - Choe, Ho-Jung

AU - Wu, Chengnan

AU - Rusanov, Daniil A.

AU - Bardina, Elena E.

AU - Kirsanova, Anna A.

AU - Zakalyukina, Yuliya V.

AU - Shmelev, Nikita Y.

AU - Tyurin, Anton P.

AU - Komarov, Vladislav Y.

AU - Kushnarev, Vladimir

AU - Karnaukhov, Nikolay S.

AU - D’Cruz, Gerald

AU - Vasilyev, Eugene S.

AU - Dotse, Eunice

AU - Chow, Kwan T.

AU - Cho, William C.

AU - Tkachev, Alexey V.

AU - Gushchin, Artem L.

AU - Babak, Maria V.

PY - 2025/10/28

Y1 - 2025/10/28

N2 - Recent studies have suggested that the commensal microbiome positively affects cancer prognosis and treatment outcomes. However, only a few strategies for regulating the microbiome composition have been reported. In this study, we identified gold(I) complexes that selectively inhibited nonbeneficial bacterial strains in vitro without affecting commensal Lactobacillus strains. In contrast, clinically used drugs demonstrated comparable effects on both commensal and noncommensal strains. Consistent with the in vitro results, the selected gold(I) complex induced favorable changes in the intratumoral and gastrointestinal microbiomes in vivo. Furthermore, its anticancer efficacy was found to be dependent on the composition of microbiome and correlated with the production of short-chain fatty acid bacterial metabolites. Structure–activity relationship studies have dissected the contribution of each structural component in both the in vivo efficacy and microbiome-modulating properties. Transcriptomic analysis of tumors revealed microbiome-associated gene signaling pathways. These findings provide valuable insights for future research on microbiome-modulating anticancer drugs, presenting potential avenues to optimize cancer treatment outcomes and mitigate side effects such as gastrointestinal dysbiosis. Furthermore, our study provides insights into the involvement of microbiome in the mechanism of action of metal-based chemotherapeutics. © 2025 the Author(s)

AB - Recent studies have suggested that the commensal microbiome positively affects cancer prognosis and treatment outcomes. However, only a few strategies for regulating the microbiome composition have been reported. In this study, we identified gold(I) complexes that selectively inhibited nonbeneficial bacterial strains in vitro without affecting commensal Lactobacillus strains. In contrast, clinically used drugs demonstrated comparable effects on both commensal and noncommensal strains. Consistent with the in vitro results, the selected gold(I) complex induced favorable changes in the intratumoral and gastrointestinal microbiomes in vivo. Furthermore, its anticancer efficacy was found to be dependent on the composition of microbiome and correlated with the production of short-chain fatty acid bacterial metabolites. Structure–activity relationship studies have dissected the contribution of each structural component in both the in vivo efficacy and microbiome-modulating properties. Transcriptomic analysis of tumors revealed microbiome-associated gene signaling pathways. These findings provide valuable insights for future research on microbiome-modulating anticancer drugs, presenting potential avenues to optimize cancer treatment outcomes and mitigate side effects such as gastrointestinal dysbiosis. Furthermore, our study provides insights into the involvement of microbiome in the mechanism of action of metal-based chemotherapeutics. © 2025 the Author(s)

KW - bioinorganic

KW - gold complex

KW - anticancer therapeutic

KW - microbiome

KW - tumor microenvironment

U2 - 10.1073/pnas.2417269122

DO - 10.1073/pnas.2417269122

M3 - RGC 21 - Publication in refereed journal

C2 - 41150715

SN - 0027-8424

VL - 122

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

IS - 44

M1 - e2417269122

ER -

Modulating the microbiome as an approach to anticancer drug development

Abstract

Funding

UN SDGs

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

Access Output

Other Access Options

Permanent Link

Fingerprint

Projects

GRF: Understanding the Myeloid-specific IRF5-mediated Immune Response in Breast Cancer

CRF-ExtU-Lead: The Immune Microenvironment of Recurrent Hepatocellular Carcinoma

HKgovt: Investigation of Gold Drug Candidates as Immunomodulating Agents for the Treatment of Malignant Pleural Mesothelioma

Cite this