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

; ; ; 
Duan, Qingling
; 
Frydrych, Ivo
; 
Rozankova, Zuzana
; ; 
Garic, Dusan
; 
Paun, Radu Alexandru
; 
Centorame, Amanda
... show 5 more
Abstract
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 bis-diethyldithiocarbamate (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 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.
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Keywords
NK cells, NKG2D, colorectal cancer, copper bis-diethyldithiocarbamate, disulfiram
Funding
This study was supported by the Ministry of Education,Youth and Sports of the Czech Republic through the project EATRIS-CZ (LM2023053) and the Technology Agency of the Czech Republic (Nanoparticle Formulation of Copper Dithiocarbamate for Cancer Treatment, FW04020197)
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Type
JournalArticle
License
Attribution 4.0 International
Date
2025-02-12
Publisher
Frontiers
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Journal Title
Frontiers in Immunology
Journal ISSN
Volume Title
DOI
10.3389/fimmu.2025.1491450
URI
https://hdl.handle.net/20.500.14620/74
Citation
Scopus
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