<p>The skin involvement (SI) of breast cancer exhibits suboptimal to standard treatment and poor prognosis. Dendritic cells (DCs) are essential to maintain immune homeostasis. However, the role of cutaneous DCs in skin lesions of breast cancer remains elusive, limiting the development of therapeutic approaches. Here, skin tissues from 47 breast cancer patients were analyzed for different immune cell infiltration, showing a significant reduction in DC number and activation in lesional skin. Transcriptome analyses, in vitro antigen processing and T lymphocyte priming assays of primary cutaneous DCs from breast cancer patients corroborated impaired antigen processing and T lymphocyte priming in lesional skin. Mechanistically, metabolomic analyses profiled the microenvironment of lesional and non-lesional skin and revealed increased prostaglandin E₂ (PGE₂) levels in the lesional skin, which could inhibit DC activation. Inhibiting PGE₂ in vivo effectively restored the activation of DCs and CD8⁺ T lymphocytes and attenuated the skin involvement in mouse models of different cancer types. Clinically, the PGE₂ levels were negatively correlated with DC infiltration in the skin of breast cancer patients, and low PGE₂ expression and high DC activation were associated with better patient outcomes. Collectively, our study reveals that PGE₂ induces DC dysfunction in the skin involvement of breast cancer, highlighting the potential of targeting PGE₂ for managing patients with skin involvement.</p><p></p>