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ARTICLE

Thimerosal Inhibits Tumor Malignant Progression through Direct Action and Enhancing the Efficacy of PD-1-Based Immunotherapy

Ping Wang1,2,#, Yan-Han Chen1,2,#, Ze-Tao Zhan1,2, Jun-Xiang Zeng1,2, Yu Chen3,4, Yuan Lin1,2, Tao Chen1,5,*, Wei-Jie Zhou1,2,5,*
1 Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
2 State Key Laboratory of Organ Failure Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
3 Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan, 528244, China
4 The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510280, China
5 Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, 341000, China
* Corresponding Author: Tao Chen. Email: email; Wei-Jie Zhou. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: Advances and Innovations in Colorectal Cancer Research and Treatment)

Oncology Research https://doi.org/10.32604/or.2025.071902

Received 14 August 2025; Accepted 11 October 2025; Published online 18 November 2025

Abstract

Background: Thimerosal is a mercury-containing preservative widely used in vaccines. This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies, particularly colorectal cancer (CRC) and melanoma. Methods: A combination of in vitro and in vivo approaches was employed. Cell proliferation, apoptosis, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8), colony formation, ATP viability, Western blotting, flow cytometry, wound-healing and Transwell assays. Subcutaneous, lung metastases, and Azoxymethane/Dextran Sulfate Sodium Salt (AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety. The functional role of mercury ions was validated using structural analogues. Mechanistic studies included RNA sequencing, Western blot, and immunohistochemical analysis of CD8+ T cell infiltration. The synergistic effect with programmed cell death protein 1 (PD-1) antibody therapy was also evaluated. Results: Thimerosal potently inhibited tumor growth (with IC50 values ranging from 0.1 to 1 μM in vitro) and significantly prolonged survival without overt toxicity in vivo. Mechanistically, mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects. Specifically, Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1) and signal transducer and activator of transcription 3 (STAT3). Furthermore, it enhanced the infiltration of CD8+ T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy. Conclusion: Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8+ T cell recruitment. It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.

Keywords

Thimerosal; colorectal cancer; melanoma; Janus kinase 1/signal transducer and activator of transcription 3; programmed cell death protein 1; immunotherapy; mercury ions; repurposed drug

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