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

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. 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. Multivariable MR identified CD20+ IgD+ CD38- naïve B cells, CD27+ unswitched memory B cells and CD3 on activated CD4 regulatory T cells as independent protective factors thyroid cancer susceptibility (OR<1, P < 0.05), supporting a potential link between thyroid cancer-susceptible B-cell phenotypes and indolent tumor behavior. Flow cytometry confirmed a significantly higher proportion of peripheral naïve B-cell in indolent compared progressive PTC (70.8% vs. 60.9%, P = 0.032). scRNA-seq revealed these subsets as the predominant tumor-infiltrating B populations in indolent PTC. In the TCGA cohort, high enrichment scores for these B-cell subsets were associated with improved T stage. Furthermore, among patients ≥55 years, high naïve B-cell scores correlated with improved disease-free survival (DFS) (HR = 0.233, P < 0.001) and overall survival (OS) (HR = 0.292, P = 0.0111), while high CD27+ memory B-cell levels were associated with better DFS (HR = 0.212, P < 0.001) and OS (HR = 0.346, P = 0.0326). 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.