Tumors with active microenvironmental type-I interferon response are sensitive to inhibitors of heme degradation

The tumor microenvironment (TME) is highly heterogeneous and plays a critical role in determining the success of therapeutic interventions. Identifying TMEs that are susceptible to specific therapies enables the development of more personalized and effective treatments. In this study, using a spontaneous murine model of breast cancer, we characterize a TME that is sensitive to inhibitors of the heme degradation pathway mediated by heme oxygenase (HO) activity, leading to CD8+ T- and NK-cell-dependent tumor control. A key feature of this TME is a chronic type-I interferon (IFN) signal, which is crucial in orchestrating an anti-tumor immune response. Notably, similar TMEs are found in human breast cancer and are associated with patient prognosis. Leveraging these insights, we demonstrate that combining a STING agonist, which induces type-I IFN responses, with an HO inhibitor results in a synergistic effect, enhancing tumor control. This study identifies HO activity as a potential resistance mechanism to type-I IFN responses, providing a novel strategy for overcoming immune evasion in cancer therapy. As part of this investigation, multiplex gene expression analysis was performed on 770 genes, including 40 housekeeping genes, from RNA extracted from MMTV-PyMT tumors. The samples were processed using the nCounter® platform, with RNA isolated, quantified, and assessed for integrity following standardized protocols, allowing for detailed molecular characterization of the TME. This study conducted a gene expression analysis to explore the tumor microenvironment (TME) in MMTV-PyMT mouse model. Tumor tissues were obtained from Prf1+/+ and Prf1-/- mice, each treated with either a vehicle or SnMP for 36 hours, totaling 12 samples (3 per condition). RNA was isolated from these tissues, quantified, and assessed for integrity. The NanoString nCounter® platform, utilizing the Pan-Cancer Immune Profiling Panel, was used to profile the expression of 770 genes, including 40 housekeeping genes.