Blocking aryl hydrocarbon receptor remodels myeloid–T cell crosstalk and enhances anti-PD-1 response in the tumor microenvironment
5 affiliations
- 1Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
- 2Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
- 3Yonsei New Il Han Institute for Integrative Lung Cancer Research, Yonsei University College of Medicine, Seoul, Korea
- 4Dong-A ST Research Institute, Yongin-si, Korea
- 5Division of Medical Oncology, Department of Internal Medicine, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40164-026-00843-8.
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BibTeX
@article{kim2026blocking,
title = {{Blocking aryl hydrocarbon receptor remodels myeloid–T cell crosstalk and enhances anti-PD-1 response in the tumor microenvironment}},
author = {Dong Kwon Kim and Sujeong Baek and Youngtaek Kim and Seung Min Yang and So Young Park and Su Jin Choi and Ju Hyeon Lee and Sang Hoon Lee and Jongho Cho and Daewon Cha and Dajeong Kim and Sunghwa Kim and Jae Hwan Kim and Byoung Chul Cho},
journal = {Experimental Hematology \& Oncology},
year = {2026},
month = oct,
doi = {10.1186/s40164-026-00843-8},
url = {https://doi.org/10.1186/s40164-026-00843-8},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Blocking aryl hydrocarbon receptor remodels myeloid–T cell crosstalk and enhances anti-PD-1 response in the tumor microenvironment
AU - Dong Kwon Kim
AU - Sujeong Baek
AU - Youngtaek Kim
AU - Seung Min Yang
AU - So Young Park
AU - Su Jin Choi
AU - Ju Hyeon Lee
AU - Sang Hoon Lee
AU - Jongho Cho
AU - Daewon Cha
AU - Dajeong Kim
AU - Sunghwa Kim
AU - Jae Hwan Kim
AU - Byoung Chul Cho
PY - 2026
DA - 2026/10/26
JO - Experimental Hematology & Oncology
DO - 10.1186/s40164-026-00843-8
UR - https://doi.org/10.1186/s40164-026-00843-8
AB - 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40164-026-00843-8.
SN - 2162-3619
ER -