Tumor microenvironments with an active type I IFN response are sensitive to inhibitors of heme degradation
Dominika Sosnowska, … , Anita Grigoriadis, James N. Arnold
Dominika Sosnowska, … , Anita Grigoriadis, James N. Arnold
Published July 8, 2025
Citation Information: JCI Insight. 2025;10(16):e191017. https://doi.org/10.1172/jci.insight.191017.
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Research Article Immunology Oncology

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

Abstract

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.

Authors

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

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Figure 3

HO inhibition facilitates type I IFN–dependent immunological control of tumor growth.

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HO inhibition facilitates type I IFN–dependent immunological control of ...
(A–F) Schematic representing the acute dosing strategy for SnMP or respective vehicle in Prf1+/+ or Prf1–/– MMTV-PyMT mice. Mice were treated with SnMP (25 μmol/kg/ daily) or vehicle for 36 hours starting on day 0 (n = 3) (A). Venn diagram showing the number of DEGs identified between the compared experimental cohorts (B). Gene Ontology (GO) analysis showing selected terms associated with enriched biological processes and pathways based on the top DEGs (C). Heatmap showing normalized median gene expression of selected genes encoding type I IFNs and type I IFN receptor subunits across groups (D). mRNA expression of Ifng and Ifnb1 relative to the housekeeping gene Tbp (cohorts of n = 5–7 mice) (E). Statistical significance was determined using a 2-sided unpaired Students t test for parametric, or Mann-Whitney test for nonparametric data. Heatmap showing normalized median gene expression of selected genes associated with type I IFN signaling (F). (G–I) Schematic representing the dosing strategy for SnMP (25 μmol/kg/daily) or respective vehicle and/or neutralizing anti-IFNAR1 antibody or control IgG in Prf1–/– MMTV-PyMT mice (G) and growth curves of treated tumors (H) and SnMP- or vehicle-treated tumors grown in mice on a Prf1–/– Ifng–/– MMTV-PyMT background (cohorts of n = 5–7 mice) (I). (J) Representative image of an FFPE tumor section from a Prf1–/– MMTV-PyMT mouse stained with DAPI (nuclei, blue), antibodies against F4/80 (red), and probed for Ifnb1 mRNA (green). Scale bar: 50 μm. Panels A and G were created using BioRender software. Statistical analysis of tumor growth curves was performed using the “CompareGrowthCurves” function of the statmod software package and bar chart was compared using a Mann-Whitney test. Bar charts show the mean and the dots show individual data points from individual tumors and mice. Line charts display the mean and SEM. *P < 0.05; **P < 0.01.