World journal of surgical oncology · 2026
Stress-driven reprogramming of plasmacytoid dendritic cells in intrahepatic cholangiocarcinoma defines a reversible targetable immunosuppressive state.
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Chen Mei-Ru, Xie Xiao-Li, Zhou Yan-Li, Tian Jin-Mei, Zhao Ying, Hou Suping, Wang Yuan-Yuan, Lu Ji-Chao, Zhao Dong-Qiang, Cui Zhao-Bo, Zhang Li-Xian
Аннотация
BACKGROUND: Plasmacytoid dendritic cells (pDCs) have been implicated in both restraining and promoting intrahepatic cholangiocarcinoma (iCCA), leaving their clinical relevance and therapeutic potential unresolved.
METHODS: Mendelian randomization was used to assess the causal association between circulating pDC levels and iCCA risk. Bulk and single-cell transcriptomic analyses were performed to characterize pDC-related programs and tumor-conditioned states, and multiplex immunofluorescence was used to define spatial distribution and clinical associations in iCCA tissues. To assess reversibility of stress-associated pDC features, IRE1α RNase activity was pharmacologically inhibited with 4µ8C under tumor-conditioned stress in vitro.
RESULTS: Genetically predicted higher circulating pDC levels were associated with lower iCCA risk, consistent with a systemic protective association. In bulk cohorts, higher expression of pDC markers (CLEC4C, NRP1, IL3RA) was associated with an immune-inflamed microenvironment and improved survival in early-stage disease. Single-cell analyses indicated that intratumoral pDCs acquired stress-associated transcriptional programs, including enrichment of endoplasmic reticulum stress and unfolded protein response pathways. In vitro, 4µ8C reduced IRE1α-dependent XBP1 splicing and partially restored type I interferon-linked activation and pDC immunogenic readouts under tumor-conditioned stress. Spatial profiling further showed that higher intratumoral CD303⁺IRF7⁺ pDC activation was associated with advanced stage and poorer overall survival, whereas higher activation in adjacent non-tumor tissues correlated with more favorable outcomes.
CONCLUSIONS: Together, these findings support a context-dependent, stress-associated pDC program in iCCA and provide a rationale for further evaluating the IRE1α-XBP1 stress axis as a potential approach to modulate pDC-associated immune states within the tumor microenvironment.
METHODS: Mendelian randomization was used to assess the causal association between circulating pDC levels and iCCA risk. Bulk and single-cell transcriptomic analyses were performed to characterize pDC-related programs and tumor-conditioned states, and multiplex immunofluorescence was used to define spatial distribution and clinical associations in iCCA tissues. To assess reversibility of stress-associated pDC features, IRE1α RNase activity was pharmacologically inhibited with 4µ8C under tumor-conditioned stress in vitro.
RESULTS: Genetically predicted higher circulating pDC levels were associated with lower iCCA risk, consistent with a systemic protective association. In bulk cohorts, higher expression of pDC markers (CLEC4C, NRP1, IL3RA) was associated with an immune-inflamed microenvironment and improved survival in early-stage disease. Single-cell analyses indicated that intratumoral pDCs acquired stress-associated transcriptional programs, including enrichment of endoplasmic reticulum stress and unfolded protein response pathways. In vitro, 4µ8C reduced IRE1α-dependent XBP1 splicing and partially restored type I interferon-linked activation and pDC immunogenic readouts under tumor-conditioned stress. Spatial profiling further showed that higher intratumoral CD303⁺IRF7⁺ pDC activation was associated with advanced stage and poorer overall survival, whereas higher activation in adjacent non-tumor tissues correlated with more favorable outcomes.
CONCLUSIONS: Together, these findings support a context-dependent, stress-associated pDC program in iCCA and provide a rationale for further evaluating the IRE1α-XBP1 stress axis as a potential approach to modulate pDC-associated immune states within the tumor microenvironment.