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

Abstract 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.