Blocking aryl hydrocarbon receptor remodels myeloid–T cell crosstalk and enhances anti-PD-1 response in the tumor microenvironment

PURPOSE: Cancer metabolism-associated immune suppression remains a major barrier to durable therapeutic responses. Indoleamine-2,3-dioxygenase 1 has been pursued as a therapeutic target, but incomplete pathway suppression has limited clinical success. As the aryl hydrocarbon receptor is a ligand-activated transcription factor and downstream effector of tryptophan metabolism, we investigated how myeloid-cell aryl hydrocarbon receptor signaling shapes the tumor immune microenvironment and whether its inhibition can restore antitumor immunity. METHODS: Conditional aryl hydrocarbon receptor knockout mice targeting dendritic cells or macrophages were used to evaluate the effects of genetic aryl hydrocarbon receptor ablation. Pharmacologic inhibition was assessed using DA-4505 across syngeneic lung, colorectal, and breast cancer models and an immune checkpoint inhibitor-refractory humanized patient-derived xenograft model. Therapeutic efficacy was evaluated alone or in combination with anti-programmed cell death protein 1 therapy, chemotherapy, or surgery. Tumor growth, survival, metastasis, and immune remodeling were analyzed by flow cytometry, multiplex immunohistochemistry, single-cell RNA sequencing, cytokine profiling, and human tumor datasets. RESULTS: Conditional aryl hydrocarbon receptor depletion in macrophages and dendritic cells enhanced innate and adaptive immune activation, increased interferon-γ-producing T cells, and strengthened antitumor immunity. In mouse tumor models, pharmacologic aryl hydrocarbon receptor blockade enhanced macrophage chemotaxis and activation programs, promoted M1-like macrophage polarization, increased interferon-γ-producing CD8⁺ T cells, and reduced regulatory T cells and polymorphonuclear myeloid-derived suppressor cells. These changes promoted robust T-cell activation and durable tumor control. Aryl hydrocarbon receptor inhibition further synergized with chemotherapy, surgery, and immune checkpoint blockade, leading to expansion of effector and memory T-cell populations and sustained antitumor responses. In a humanized lung cancer model, aryl hydrocarbon receptor blockade increased intratumoral CD8⁺ T-cell infiltration and cytotoxic-memory programs while reducing regulatory T-cell enrichment. In human tumor datasets, aryl hydrocarbon receptor-positive macrophages correlated with FOXP3⁺ T-cell infiltration, and higher aryl hydrocarbon receptor inhibition-associated T-cell signatures were associated with improved patient survival.