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Assessment of the impact of multi-cancer early detection test screening intervals on late-stage cancer at diagnosis and mortality using a state-transition model
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  • Published on: 22 May 2025
    Beyond Detection: The Immunomodulatory Role of Methylated cfDNA in Tumor Immune Evasion
    • Joseph Bellanti, Clinical Immunologist Georgetown University Medical Center
    • Other Contributors:
      • Dongmei Li, Research Microbiologist

    To the Editor:

    I read with great interest the recent article by Rous et al. (BMJ Open 2025;15:e086648), which presents an important modeling analysis of screening intervals for multi-cancer early detection (MCED) tests based on cell-free DNA (cfDNA) methylation profiling. The work underscores the growing utility of cfDNA-based diagnostics in detecting cancer-specific epigenetic signatures with high specificity.
    However, I would like to respectfully offer an additional perspective that may have been overlooked, namely, the active immunologic role of methylated DNA in modulating tumor immunity. Based on our group's published work, we have shown that methylated DNA, particularly methylated CpG motifs, can directly stimulate the differentiation of Foxp3+ regulatory T cells (Tregs) (1-4). This immunologic pathway contributes to immune tolerance and may facilitate tumor immune evasion.
    While current MCED models consider methylation purely as a passive biomarker of malignancy, it is important to recognize that the same methylated cfDNA fragments detected in plasma may also exert biologic effects on the host immune system. In particular, their capacity to expand Treg populations could help explain why some tumors remain clinically silent or escape immune surveillance, even when detectable at early stages by cfDNA analysis.
    This dual role—diagnostic and immunoregulatory—has implications for both the interpretation of MCED test resul...

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    Conflict of Interest:
    None declared.