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Background <p>Wilms tumor (WT), the most common pediatric malignant renal tumor, shows high recurrence in high-risk subtypes due to chemoresistance. Tumor microenvironment (TME) remodeling, particularly M2-type tumor-associated macrophages (TAMs), contributes to chemoresistance, but underlying mechanisms remain unclear. This study explored TME-related chemoresistance mechanisms in WT and developed targeted therapeutic strategies.</p> Methods <p>Clinical WT samples were analyzed for M2-type TAMs infiltration and SNRPC expression. Bioinformatics analysis of TARGET-WT data identified M2-associated genes. In vitro experiments (cell transfection, qRT-PCR, Western blot, co-culture, ChIP and dual-luciferase reporter assays) explored SNRPC’s role in regulating M2-type TAMs. Animal models (orthotopic tumor and lung metastasis) verified in vivo effects. A hybrid exosome nanosystem (DOX/siSNRPC@hEVs) was constructed and evaluated for efficacy and safety. Statistical analyses included t-test, ANOVA, and survival analysis.</p> Results <p>M2-type TAMs (CD68⁺CD163⁺) infiltration was higher in chemoresistant WT and associated with poor prognosis. SNRPC was overexpressed in chemoresistant WT, correlated with M2-type TAMs, and promoted tumor malignancy and M2-type TAMs polarization. Mechanistically, SNRPC activated NF-κB signaling, inducing CXCL17 upregulation to recruit M2-type TAMs, with partial CXCL17 release via migrasomes. DOX/siSNRPC@hEVs showed high targeting, reduced toxicity, inhibited tumor growth/metastasis, and reversed chemoresistance by reducing M2-type TAMs.</p> Conclusions <p>The SNRPC-NF-κB-CXCL17-M2 TAMs axis drives WT chemoresistance. DOX/siSNRPC@hEVs effectively targets this axis, providing a novel strategy for high-risk WT.</p> Graphical abstract <p></p>

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SNRPC promotes chemoresistance in Wilms tumor via the NF-κB-CXCL17 axis regulating M2-Type TAMs infiltration and targeted nanotherapy research

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月28日

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  • Xiangpan Kong,
  • Li Lei,
  • Liming Jin,
  • Chunnian Ren,
  • Tao Mi,
  • Quan Wang,
  • Dawei He

摘要

Background

Wilms tumor (WT), the most common pediatric malignant renal tumor, shows high recurrence in high-risk subtypes due to chemoresistance. Tumor microenvironment (TME) remodeling, particularly M2-type tumor-associated macrophages (TAMs), contributes to chemoresistance, but underlying mechanisms remain unclear. This study explored TME-related chemoresistance mechanisms in WT and developed targeted therapeutic strategies.

Methods

Clinical WT samples were analyzed for M2-type TAMs infiltration and SNRPC expression. Bioinformatics analysis of TARGET-WT data identified M2-associated genes. In vitro experiments (cell transfection, qRT-PCR, Western blot, co-culture, ChIP and dual-luciferase reporter assays) explored SNRPC’s role in regulating M2-type TAMs. Animal models (orthotopic tumor and lung metastasis) verified in vivo effects. A hybrid exosome nanosystem (DOX/siSNRPC@hEVs) was constructed and evaluated for efficacy and safety. Statistical analyses included t-test, ANOVA, and survival analysis.

Results

M2-type TAMs (CD68⁺CD163⁺) infiltration was higher in chemoresistant WT and associated with poor prognosis. SNRPC was overexpressed in chemoresistant WT, correlated with M2-type TAMs, and promoted tumor malignancy and M2-type TAMs polarization. Mechanistically, SNRPC activated NF-κB signaling, inducing CXCL17 upregulation to recruit M2-type TAMs, with partial CXCL17 release via migrasomes. DOX/siSNRPC@hEVs showed high targeting, reduced toxicity, inhibited tumor growth/metastasis, and reversed chemoresistance by reducing M2-type TAMs.

Conclusions

The SNRPC-NF-κB-CXCL17-M2 TAMs axis drives WT chemoresistance. DOX/siSNRPC@hEVs effectively targets this axis, providing a novel strategy for high-risk WT.

Graphical abstract