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Peer-reviewedCC BY 4.0Frontiers in Immunology

Multiple sources, shared readouts: the attribution gap in circular RNA immunotherapy for esophageal squamous cell carcinoma

  • Zhenhua Li1
  • Jiawen Wang1
  • Huilai Lv1
  • Fan Zhang1
  • Bokang Sun1
  • Chao Huang1
  • Zhao Liu1
  • Ziqiang Tian1
  1. 1Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University
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Abstract

Therapeutic circular RNAs (circRNAs) are progressing from preclinical development to clinical evaluation, and esophageal squamous cell carcinoma (ESCC) may become a future indication for circRNA-based immunotherapy, potentially including first-line use. However, three focal sources—the intrinsic immunogenicity of exogenous circRNAs, the abundance of the endogenous circRNA pool, and patients’ baseline interferon states—can act through different mechanisms but converge on the same readouts, including interferon output, protein yield, and immune phenotypes. Their individual contributions are therefore difficult to distinguish, complicating efforts to establish dose–response relationships. This Perspective examines this structural barrier to effect attribution and proposes strategies at three levels: product characterization and control, effect dissection, and baseline adjustment. We argue that studies of circRNA immunotherapy in ESCC and related settings should incorporate concurrent measurement of these three key, measurable sources at the design stage, with causal inference complementing association analyses to grade the reliability of attribution. Such an approach could help reduce attribution bias and provide a foundation for subsequent dose optimization and risk stratification.

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Cite

BibTeXRIS
BibTeX
@article{li2026multiple,
  title = {{Multiple sources, shared readouts: the attribution gap in circular RNA immunotherapy for esophageal squamous cell carcinoma}},
  author = {Zhenhua Li and Jiawen Wang and Huilai Lv and Fan Zhang and Bokang Sun and Chao Huang and Zhao Liu and Ziqiang Tian},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1985510},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1985510/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Multiple sources, shared readouts: the attribution gap in circular RNA immunotherapy for esophageal squamous cell carcinoma
AU  - Zhenhua Li
AU  - Jiawen Wang
AU  - Huilai Lv
AU  - Fan Zhang
AU  - Bokang Sun
AU  - Chao Huang
AU  - Zhao Liu
AU  - Ziqiang Tian
PY  - 2026
DA  - 2026/10/21
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1985510
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1985510/full
AB  - Therapeutic circular RNAs (circRNAs) are progressing from preclinical development to clinical evaluation, and esophageal squamous cell carcinoma (ESCC) may become a future indication for circRNA-based immunotherapy, potentially including first-line use. However, three focal sources—the intrinsic immunogenicity of exogenous circRNAs, the abundance of the endogenous circRNA pool, and patients’ baseline interferon states—can act through different mechanisms but converge on the same readouts, including interferon output, protein yield, and immune phenotypes. Their individual contributions are therefore difficult to distinguish, complicating efforts to establish dose–response relationships. This Perspective examines this structural barrier to effect attribution and proposes strategies at three levels: product characterization and control, effect dissection, and baseline adjustment. We argue that studies of circRNA immunotherapy in ESCC and related settings should incorporate concurrent measurement of these three key, measurable sources at the design stage, with causal inference complementing association analyses to grade the reliability of attribution. Such an approach could help reduce attribution bias and provide a foundation for subsequent dose optimization and risk stratification.
SN  - 1664-3224
ER  -