Glucocorticoid receptor inhibition enables tumor-infiltrating macrophages to overcome immunotherapy resistance in advanced melanoma

Immune-checkpoint inhibitors (ICIs) benefit patients with advanced melanoma, yet resistance remains common and the myeloid circuits that limit response are incompletely defined. We identify glucocorticoid receptor (GR) signaling in tumor-associated macrophages (TAMs) as a druggable brake on antitumor immunity under PD 1 blockade. Myeloid-specific GR deletion restored immune recognition and overcame anti-PD 1 resistance, resulting in restrained melanoma growth. CITE-seq revealed that GR loss reprogrammed multiple TAM subsets towards interferon-licensed, antigen-presenting, chemokine-producing states, reshaping T cell composition toward cytotoxic effector and tissue-resident memory phenotypes with attenuated exhaustion. Cross-species analyses linked glucocorticoid activity and GR-regulated myeloid and T cell states to clinical response. To therapeutically exploit this axis, we engineered CD169-targeted lipid nanoparticles delivering the GR antagonist mifepristone to TAMs. Targeted GR antagonism re-educated the immune niche, restored T cell stimulatory capacity, and synergized with PD 1 blockade in ICI-refractory melanoma. These data nominate myeloid GR inhibition as a biomarker-guided strategy to enhance ICI efficacy.