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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]