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Background <p>Triple-negative breast cancer (TNBC) remains difficult to treat because of poor immunogenicity and an immunosuppressive tumor microenvironment (TME). Pyroptotic signaling can enhance antitumor immunity through inflammatory cytokine release, but upstream regulators linking this process to macrophage phenotypic remodeling in TNBC remain incompletely understood. We investigated whether zinc finger protein 831 (ZNF831) restrains TNBC progression in association with enhanced NLR family pyrin domain containing 3 (NLRP3)-related pyroptotic signaling and macrophage phenotypic remodeling.</p> Methods <p>We integrated The Cancer Genome Atlas (TCGA-BRCA), Gene Expression Omnibus bulk datasets (GSE103091, GSE176078), and breast cancer single-cell RNA-sequencing datasets from Tumor Immune Single-cell Hub 2 (BRCA_GSE114727_inDrop, BRCA_GSE148673, BRCA_GSE150660, and BRCA_GSE161529) to evaluate ZNF831 expression, prognosis, pathway enrichment, and macrophage-related immune features. ZNF831 was overexpressed or silenced in MDA-MB-231 and 4T1-luc cells to assess macrophage recruitment, macrophage phenotypic changes, NLRP3-associated pyroptotic signaling, and IL-1β/IL-18 release. Chromatin immunoprecipitation (ChIP)-qPCR, actinomycin D chase assays, and RNA immunoprecipitation (RIP)-qPCR were performed primarily in MDA-MB-231 cells to evaluate promoter association, mRNA stability, and transcript interaction. In vivo efficacy was assessed in 6-week-old female BALB/c mice bearing orthotopic 4T1-luc tumors treated intratumorally with MCC950 or PBS.</p> Results <p>Across cohorts, higher ZNF831 expression was associated with favorable outcome, an M1-skewed macrophage signature, and enrichment of pyroptosis-related pathways. In vitro, ZNF831 overexpression enhanced macrophage recruitment, shifted macrophage phenotypes toward a more pro-inflammatory M1-like state while suppressing M2-like features, promoted NLRP3-associated pyroptotic signaling, and increased IL-1β and IL-18 release, whereas ZNF831 knockdown produced opposite trends. Mechanistically, ZNF831 showed association with the NLRP3 promoter and selective enrichment of NLRP3 mRNA, consistent with multi-level regulation of NLRP3 expression. In vivo, pharmacologic inhibition with MCC950 attenuated the antitumor effects and macrophage-related changes associated with ZNF831 overexpression.</p> Conclusions <p>These findings support a role for the ZNF831–NLRP3 axis in shaping a more inflammatory TNBC microenvironment and suggest that ZNF831 may contribute to macrophage M1-like phenotypic remodeling through NLRP3-associated pyroptotic signaling.</p>

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ZNF831 suppresses triple-negative breast cancer progression through NLRP3-associated pyroptotic signaling and M1-like macrophage phenotypic remodeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月23日

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  • Qingqing Liu,
  • Jun Fan,
  • Wantao Peng,
  • Shuangwu Deng,
  • Yupei Tan,
  • Fei Guo,
  • Jiangxue Zhong,
  • Shimeng Zhou,
  • Wenbin Liu,
  • Yan Xu

摘要

Background

Triple-negative breast cancer (TNBC) remains difficult to treat because of poor immunogenicity and an immunosuppressive tumor microenvironment (TME). Pyroptotic signaling can enhance antitumor immunity through inflammatory cytokine release, but upstream regulators linking this process to macrophage phenotypic remodeling in TNBC remain incompletely understood. We investigated whether zinc finger protein 831 (ZNF831) restrains TNBC progression in association with enhanced NLR family pyrin domain containing 3 (NLRP3)-related pyroptotic signaling and macrophage phenotypic remodeling.

Methods

We integrated The Cancer Genome Atlas (TCGA-BRCA), Gene Expression Omnibus bulk datasets (GSE103091, GSE176078), and breast cancer single-cell RNA-sequencing datasets from Tumor Immune Single-cell Hub 2 (BRCA_GSE114727_inDrop, BRCA_GSE148673, BRCA_GSE150660, and BRCA_GSE161529) to evaluate ZNF831 expression, prognosis, pathway enrichment, and macrophage-related immune features. ZNF831 was overexpressed or silenced in MDA-MB-231 and 4T1-luc cells to assess macrophage recruitment, macrophage phenotypic changes, NLRP3-associated pyroptotic signaling, and IL-1β/IL-18 release. Chromatin immunoprecipitation (ChIP)-qPCR, actinomycin D chase assays, and RNA immunoprecipitation (RIP)-qPCR were performed primarily in MDA-MB-231 cells to evaluate promoter association, mRNA stability, and transcript interaction. In vivo efficacy was assessed in 6-week-old female BALB/c mice bearing orthotopic 4T1-luc tumors treated intratumorally with MCC950 or PBS.

Results

Across cohorts, higher ZNF831 expression was associated with favorable outcome, an M1-skewed macrophage signature, and enrichment of pyroptosis-related pathways. In vitro, ZNF831 overexpression enhanced macrophage recruitment, shifted macrophage phenotypes toward a more pro-inflammatory M1-like state while suppressing M2-like features, promoted NLRP3-associated pyroptotic signaling, and increased IL-1β and IL-18 release, whereas ZNF831 knockdown produced opposite trends. Mechanistically, ZNF831 showed association with the NLRP3 promoter and selective enrichment of NLRP3 mRNA, consistent with multi-level regulation of NLRP3 expression. In vivo, pharmacologic inhibition with MCC950 attenuated the antitumor effects and macrophage-related changes associated with ZNF831 overexpression.

Conclusions

These findings support a role for the ZNF831–NLRP3 axis in shaping a more inflammatory TNBC microenvironment and suggest that ZNF831 may contribute to macrophage M1-like phenotypic remodeling through NLRP3-associated pyroptotic signaling.