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Simple Summary: Drug development and therapeutic approaches for treating cancer have shifted towards incorporating more multimodality approaches that harness the immune system. Despite innovative and notable advances in immunotherapy, challenges associated with variations in patient response rates and efficacies on select tumors minimize the overall effectiveness of these immunotherapy approaches. This review provides an overview of the current immunotherapy options available, followed by epigenetic immunomodulators that may enhance and transmogrify immunotherapy effectiveness. These approaches are positioned to harness trained immunity, improve immune response rates, and increase the efficacy of immunotherapies. Cancer immunotherapy harnesses the immune system by targeting tumor cells that express antigens recognized by immune system cells, thus leading to tumor rejection. These tumor-associated antigens include tumor-specific shared antigens, differentiation antigens, protein products of mutated genes and rearrangements unique to tumor cells, overexpressed tissue-specific antigens, and exogenous viral proteins. However, the development of effective therapeutic approaches has proven difficult, mainly because these tumor antigens are shielded, and cells primarily express self-derived antigens. Despite innovative and notable advances in immunotherapy, challenges associated with variable patient response rates and efficacy on select tumors minimize the overall effectiveness of immunotherapy. Variations observed in response rates to immunotherapy are due to multiple factors, including adaptative resistance, competency, and a diversity of individual immune systems, including cancer stem cells in the tumor microenvironment, composition of the gut microbiota, and broad limitations of current immunotherapeutic approaches. New approaches are positioned to improve the immune response and increase the efficacy of immunotherapies, highlighting the challenges that the current global COVID-19 pandemic places on the present state of immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer presents a unique clinical problem because of the variety of cellular subtypes present, including cancer stem cells (CSCs). Breast CSCs can induce the formation of new blood vessels at the site of tumor growth and a develop metastatic phenotype by enhancing a stromal cell response, similar to that of the primary breast cancer. The aim of this study was to investigate breast cancer cells cultured in stromal stem cell factor-supplemented media to generate 3D spheroids that exhibit increased stem-like properties. These 3D stem-like spheroids reproducibly and efficiently established orthotopic breast cancer xenografts in the athymic nude rat. This approach enables a means to develop orthotopic tumors with a stem-like phenotype in a larger athymic rat rodent model of human breast cancer. Therapeutic targeting of stem cells needs to be strategically developed to control tumor growth and prevent metastatic burden successfully. Breast cancer presents a unique clinical problem because of the variety of cellular subtypes present, including cancer stem cells (CSCs). The development of 3D stem-like properties of human breast tumor spheroids in stem cell factor conditioned media was investigated in orthotopic xenografts for enhanced tumorgenicity in the athymic nude rat model. MCF-7, ZR-75-1, and MDA-MB-231 breast cancer cell lines were cultured in serum-free, stem cell factor-supplemented medium under non-adherent conditions and passaged to generate 3rd generation spheroids. The spheroids were co-cultured with fetal lung fibroblast (FLF) cells before orthotopic heterotransplantation into the mammary fat pads of athymic nude rats. Excised xenografts were assessed histologically by H&E staining and immunohistochemistry for breast cancer marker (ERB1), proliferation marker (Ki67), mitotic marker (pHH3), hypoxia marker (HIF-2α), CSC markers (CD47, CD44, CD24, and CD133), and vascularization markers (CD31, CD34). Breast cancer cells cultured in stem cell factor supplemented medium generated 3D spheroids exhibited increased stem-like characteristics. The 3D stem-like spheroids co-cultured with FLF as supporting stroma reproducibly and efficiently established orthotopic breast cancer xenografts in the athymic nude rat. [ABSTRACT FROM AUTHOR]