Journal Article

Tumor microenvironments with an active type I IFN response are sensitive to inhibitors of heme degradation

Anstee, Joanne E., Clayton, Kalum, Yang, Dorothy D., Buus, Richard, Opzoomer, James W., Keddar, Mohamed Reda, Ali, Samira, Sosnowska, Dominika, Grigoriadis, Anita, Cheung, Tik Shing, Feehan, Karen T., Rosekilly, James, Spicer, James, Sarkar, Jit, Arnold, James N., Woodman, Chloé A., Gillett, Cheryl E., Macmorland, William, Ciccarelli, Francesca D.

2025

Overview

The tumor microenvironment (TME) is highly heterogeneous and can dictate the success of therapeutic interventions. Identifying TMEs that are susceptible to specific therapeutic interventions paves the way for more personalized and effective treatments. In this study, using a spontaneous murine model of breast cancer, we characterize a TME that is responsive to inhibitors of the heme degradation pathway mediated by heme oxygenase (HO), resulting in CD8+ T cell- and NK cell-dependent tumor control. A hallmark of this TME is a chronic type I interferon (IFN) signal that is directly involved in orchestrating the antitumor immune response. Importantly, we identify that similar TMEs exist in human breast cancer that are associated with patient prognosis. Leveraging these observations, we demonstrate that combining a STING agonist, which induces type I IFN responses, with an HO inhibitor produces a synergistic effect leading to superior tumor control. This study highlights HO activity as a potential resistance mechanism for type I IFN responses in cancer, supporting a therapeutic rationale for targeting the heme degradation pathway to enhance the efficacy of STING agonists.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Agonists / Animal models / Animals / Antitumor activity / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - immunology / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell Line, Tumor / Clinical outcomes / Degradation / Disease Models, Animal / Female / Heme - metabolism / Heme oxygenase (decyclizing) / Heme Oxygenase (Decyclizing) - antagonists & inhibitors / Heme Oxygenase (Decyclizing) - metabolism / Humans / Immune response / Immunology / Immunotherapy / Interferon / Interferon Type I - immunology / Interferon Type I - metabolism / Investigations / Killer Cells, Natural - immunology / Lymphocytes / Lymphocytes T / Medical prognosis / Membrane Proteins - agonists / Mice / Natural killer cells / Oncology / Signal Transduction - drug effects / Software / Therapeutic applications / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors