Unraveling the indolence of papillary thyroid carcinoma: an exploratory study on B-cell subsets based on genetic predisposition and tumor immunity.

Background: Active surveillance for low-risk papillary thyroid carcinoma (PTC) is hampered by the lack of reliable biomarkers to distinguish indolent from progressive tumors. While our previous single-cell analysis identified tumor-infiltrating B cells as key determinants of indolent PTC, their clinical utility remains constrained by low abundance and peripheral undetectability. We therefore employed Mendelian randomization (MR) to investigate this causal relationship and assess the potential of peripheral B-cell profiling as a non-invasive strategy for distinguishing indolent PTC. Methods: We integrated MR, flow cytometry, single-cell transcriptomics, and clinical validation. A two-sample MR framework was used to assessed causal relationships between immunophenotypes and thyroid cancer risk. Findings were exploratorily investigated by flow cytometric comparison of B-cell subsets between indolent and progressive PTC patients, further characterized using single-cell RNA sequencing data, and evaluated for prognostic significance in the TCGA-THCA cohort. Results: Multivariable MR identified CD20+ IgD+ CD38 Conclusion: This study provides exploratory genetic and clinical evidence supporting a causal, protective role for specific peripheral and tumor-infiltrating B-cell subsets in PTC. Naïve B cells and CD27+ unswitched memory B cells are linked to indolent tumor behavior and favorable prognosis, highlighting their potential as biomarkers for risk stratification and non-invasive monitoring in PTC management.