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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1491450
This article is part of the Research Topic Crosstalk in Tumor Microenvironments: Shaping Early Drug and Immunotherapy Strategies View all 6 articles

Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis

Provisionally accepted
Daciana Catalina Dumut Daciana Catalina Dumut 1Marian Hajduch Marian Hajduch 2Amanda M Zacharias Amanda M Zacharias 3Qingling Duan Qingling Duan 3Ivo Frydrych Ivo Frydrych 2Zuzana Rozankova Zuzana Rozankova 2Miroslav Popper Miroslav Popper 2Dusan Garic Dusan Garic 4Radu Alexandru Paun Radu Alexandru Paun 1Amanda Centorame Amanda Centorame 1Juhi Shah Juhi Shah 1Martin Mistrik Martin Mistrik 2Petr Dzubak Petr Dzubak 2Juan Bautista De Sanctis Juan Bautista De Sanctis 2Danuta Radzioch Danuta Radzioch 1,2*
  • 1 McGill University, Montreal, Canada
  • 2 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Olomouc, Czechia
  • 3 Queen's University, Kingston, Ontario, Canada
  • 4 St. Jude Children's Research Hospital, Memphis, Tennessee, United States

The final, formatted version of the article will be published soon.

    Advanced metastatic colorectal cancer (CRC) with deficient DNA mismatch repair (MMR-d), or immune-hot CRCs, show significantly improved clinical outcomes compared to MMR-proficient (MMR-p), or immune-cold CRCs. While the prior represents about 5% of all CRCs, the latter represent 95% and are characterized by low immunogenicity. This study investigates bisdiethyldithiocarbamate (CuET), a novel anticancer compound, and its impact on the colorectal cancer tumor microenvironment (TME). CuET is shown to convert immunologically inactive tumors into hotbeds of antitumor immune responses, marked by increased lymphocyte infiltration, heightened cytotoxicity of natural killer (NK) and T cells, and enhanced non-self recognition by lymphocytes. The potent anticancer cytotoxicity and in vivo safety and efficacy of CuET are established. In summary, CuET transforms the colorectal cancer TME, bolstering NK and T cell cytotoxicity and refining tumor cell recognition through non-classical activation via the NKG2D/ NKG2DL axis. This study unveils a novel mechanism of action for CuET: a potent immunomodulator capable of turning cold tumors hot.

    Keywords: Copper bis-diethyldithiocarbamate, Disulfiram, colorectal cancer, NK cells, NKG2D

    Received: 04 Sep 2024; Accepted: 17 Jan 2025.

    Copyright: © 2025 Dumut, Hajduch, Zacharias, Duan, Frydrych, Rozankova, Popper, Garic, Paun, Centorame, Shah, Mistrik, Dzubak, De Sanctis and Radzioch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Danuta Radzioch, McGill University, Montreal, Canada

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.