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<p>Dendritic cells (DC) dysfunction impedes antitumor immunity, so understanding intrinsic regulators of DC antigen presentation and the resulting activation of antitumor CD8<sup>+</sup> T cells could benefit therapy. Here, we use a genome-wide CRISPR screen for antigen presentation-regulating genes in DCs, and identify estrogen receptor α (ERα) as an intrinsic checkpoint inhibiting antigen cross-presentation. ERα genomic deficiency or pharmacological degradation enhances antigen presentation and CD8<sup>+</sup> T cell priming in mouse and human DCs. Mechanistically, independently of canonical estrogen signaling, ERα sustains Galectin-3-mediated recruitment of CHMP4b to damaged phagosomes, thereby facilitating ESCRT-III-mediated membrane repair and restricting cytosolic antigen translocation. In vivo, ERα-deficient or ERα-degraded DC vaccines expand tumor-specific CD8<sup>+</sup> T cells to suppress tumor growth in mice bearing subcutaneous cancers. In vitro, FDA-approved ERα antagonists enhance human DC-mediated activation of antigen-specific human CD8<sup>+</sup> T cells. Our work thus uncovers a non-canonical role of ERα in phagosome integrity as a checkpoint for antigen cross-presentation in DCs, and implicates ERα-targeted DC vaccines as a potential immunotherapeutic strategy.</p>

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ERα blockade in dendritic cells enhances antigen cross-presentation and induces antitumor CD8+ T cell immunity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月5日

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  • Yaxin Liu,
  • Zhongfei Ma,
  • Xuelian Li,
  • Yuanyuan Ding,
  • Zhiqing Li,
  • Bin Zhang,
  • Yumei Zhou,
  • Jun Zhou,
  • Shuo Liu,
  • Shuxun Liu,
  • Lianjun Zhang,
  • Chunmei Wang,
  • Xuetao Cao

摘要

Dendritic cells (DC) dysfunction impedes antitumor immunity, so understanding intrinsic regulators of DC antigen presentation and the resulting activation of antitumor CD8+ T cells could benefit therapy. Here, we use a genome-wide CRISPR screen for antigen presentation-regulating genes in DCs, and identify estrogen receptor α (ERα) as an intrinsic checkpoint inhibiting antigen cross-presentation. ERα genomic deficiency or pharmacological degradation enhances antigen presentation and CD8+ T cell priming in mouse and human DCs. Mechanistically, independently of canonical estrogen signaling, ERα sustains Galectin-3-mediated recruitment of CHMP4b to damaged phagosomes, thereby facilitating ESCRT-III-mediated membrane repair and restricting cytosolic antigen translocation. In vivo, ERα-deficient or ERα-degraded DC vaccines expand tumor-specific CD8+ T cells to suppress tumor growth in mice bearing subcutaneous cancers. In vitro, FDA-approved ERα antagonists enhance human DC-mediated activation of antigen-specific human CD8+ T cells. Our work thus uncovers a non-canonical role of ERα in phagosome integrity as a checkpoint for antigen cross-presentation in DCs, and implicates ERα-targeted DC vaccines as a potential immunotherapeutic strategy.