Looking for a cure for cancer has been a priority for scientists for over 250 years now, and with 19.3 million new cases recorded globally in 2020, this is becoming even more urgent. If cancerous tumor cells are developed within our own body, the most effective treatment mechanism would be to redirect the body’s natural defenses to identify and destroy these cancerous cells. This study addresses the critical gap in understanding the role of IFN experience in the regulation of cancer stem cell (CSC) marker expression in sarcoma, a rare, aggressive cancer type. Leveraging an MX1-Cre-tdTomato mice reporter model, it explores the effects of IFN exposure on CSC markers’ expression, hypothesizing that IFN experience enhances the stem-like properties of these cells. This research is divided into two areas of focus: bone marrow macrophages and tumor cells derived from the reporter models. While bone marrow macrophages did not show significant results, a notable difference in endocytosis activity between red (IFN- experienced) and non-red (IFN-naive) spleen macrophages was observed. Type I IFN treatment influenced the growth, proliferation, and CSC marker expression in tumor cells differently based on their IFN experience, with non-red cells becoming more stem-like. The research also revealed a potential role of sodium butyrate in modulating hey1 expression, a gene associated with the Notch signaling pathway and tumor progression. These findings advance our understanding of the complex interplay between IFN treatment, gene expression, and cellular characteristics in tumor biology, which could provide novel therapeutic targets.