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

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. Dendritic cells (DC) present antigens leading to CD8+ T cell activation and can induce antitumor immunity. Here, the authors perform a CRISPR screen and identify ERα as a negative regulator of antigen cross-presentation, with ERα-deficient or ERα-degraded DC vaccines potentiating antitumor responses in vivo.