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Thimerosal Inhibits Tumor Malignant Progression through Direct Action and Enhancing the Efficacy of PD-1-Based
Ping Wang1,2, Yan-Han Chen1,2, Ze-Tao Zhan1,2
1Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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.
Insights
Thimerosal shows antitumor effects in colorectal cancer and melanoma by inhibiting JAK1/STAT3 and boosting CD8+ T cell infiltration. This mercury-containing compound may be a promising repurposed drug and immunotherapy adjuvant.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Thimerosal, a mercury-containing vaccine preservative, is investigated for potential antitumor properties.
- Solid malignancies, specifically colorectal cancer (CRC) and melanoma, are the focus of this study.
- The study explores the mechanisms underlying Thimerosal's effects on cancer cells and the tumor microenvironment.
Purpose of the Study:
- To evaluate the antitumor efficacy of Thimerosal in colorectal cancer and melanoma models.
- To elucidate the molecular mechanisms by which Thimerosal exerts its anticancer effects.
- To assess the safety and potential synergistic effects of Thimerosal with immunotherapy.
Main Methods:
- Utilized in vitro and in vivo models, including cell culture assays (CCK-8, colony formation, ATP viability) and animal models (subcutaneous, lung metastasis, AOM/DSS-induced CRC).
- Assessed cell proliferation, apoptosis, migration, and invasion using Western blotting, flow cytometry, wound-healing, and Transwell assays.
- Investigated mechanistic pathways through RNA sequencing, Western blot, immunohistochemistry for CD8+ T cell infiltration, and evaluated synergy with anti-PD-1 therapy.
Main Results:
- Thimerosal demonstrated potent inhibition of tumor growth in vitro (IC50: 0.1-1 μM) and prolonged survival in vivo with minimal toxicity.
- Mercury ions were identified as key mediators of Thimerosal's antitumor activity, inhibiting JAK1/STAT3 phosphorylation.
- Thimerosal increased CD8+ T cell infiltration into tumors and enhanced the efficacy of anti-PD-1 therapy.
Conclusions:
- Thimerosal exhibits dual antitumor actions: direct inhibition of JAK1/STAT3 signaling and immune modulation through CD8+ T cell recruitment.
- Thimerosal shows promise as a repurposed drug for colorectal cancer and melanoma.
- Its role as an immunotherapeutic adjuvant, particularly in combination with anti-PD-1 therapy, warrants further investigation.
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