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Simple Summary: Ewing Sarcoma treatment is traditionally based on chemotherapy, surgery, and radiotherapy. Although these standard of care regimens are efficient at early disease stages, many patients fail to respond appropriately, which has prompted the search for more efficacious and specific treatments. A deeper understanding of the basic molecular mechanisms underlying the biology of both tumor cells and the tumor microenvironment, as well as advances in drug delivery, has led to the development of different approaches to improve the treatment in Ewing Sarcoma patients. Thus, epigenetic, and immunotherapy-based drugs, along with nanotechnology delivery strategies, represent novel preclinical and clinical studies in the treatment of Ewing Sarcoma. In this review, we provide a comprehensive overview of these emerging therapeutic strategies and summarize the potential of the latest preclinical and clinical trials in Ewing Sarcoma research. Finally, we underline the value and future directions of these new treatments. Ewing Sarcoma (EWS) is an aggressive bone and soft tissue tumor that mainly affects children, adolescents, and young adults. The standard therapy, including chemotherapy, surgery, and radiotherapy, has substantially improved the survival of EWS patients with localized disease. Unfortunately, this multimodal treatment remains elusive in clinics for those patients with recurrent or metastatic disease who have an unfavorable prognosis. Consistently, there is an urgent need to find new strategies for patients that fail to respond to standard therapies. In this regard, in the last decade, treatments targeting epigenetic dependencies in tumor cells and the immune system have emerged into the clinical scenario. Additionally, recent advances in nanomedicine provide novel delivery drug systems, which may address challenges such as side effects and toxicity. Therefore, therapeutic strategies stemming from epigenetics, immunology, and nanomedicine yield promising alternatives for treating these patients. In this review, we highlight the most relevant EWS preclinical and clinical studies in epigenetics, immunotherapy, and nanotherapy conducted in the last five years. [ABSTRACT FROM AUTHOR]

Simple Summary: Lymphoma and other cancers have been studied by mainly focusing on malignant cells. However, research findings about the role of the tumor microenvironment in the progression and immunosuppression of cancer, particularly in lymphomas, have increased considerably in recent years, allowing for a better understanding of the disease. Consequently, epigenetic mechanisms that are implicated in the interplay between tumor cells and the different components around them, promoting the survival and progression of the tumor, have been described. This review tries to summarize the complex interplay between lymphoma tumor cells and immune cells as well as the epigenetic alterations that result from this cross-talk, aiming at contributing towards underlining the value of epigenetic modifications as new biomarkers and the use of epigenetic drugs as an interesting therapeutic option. Lymphoma is a neoplasm arising from B or T lymphocytes or natural killer cells characterized by clonal lymphoproliferation. This tumor comprises a diverse and heterogeneous group of malignancies with distinct clinical, histopathological, and molecular characteristics. Despite advances in lymphoma treatment, clinical outcomes of patients with relapsed or refractory disease remain poor. Thus, a deeper understanding of molecular pathogenesis and tumor progression of lymphoma is required. Epigenetic alterations contribute to cancer initiation, progression, and drug resistance. In fact, over the past decade, dysregulation of epigenetic mechanisms has been identified in lymphomas, and the knowledge of the epigenetic aberrations has led to the emergence of the promising epigenetic therapy field in lymphoma tumors. However, epigenetic aberrations in lymphoma not only have been found in tumor cells, but also in cells from the tumor microenvironment, such as immune cells. Whereas the epigenetic dysregulation in lymphoma cells is being intensively investigated, there are limited studies regarding the epigenetic mechanisms that affect the functions of immune cells from the tumor microenvironment in lymphoma. Therefore, this review tries to provide a general overview of epigenetic alterations that affect both lymphoma cells and infiltrating immune cells within the tumor, as well as the epigenetic cross-talk between them. [ABSTRACT FROM AUTHOR]

The presence of the chimeric EWSR1-FLI1 oncoprotein is the main and initiating event defining Ewing sarcoma (ES). The dysregulation of epigenomic and proteomic homeostasis induced by the oncoprotein contributes to a wide variety of events involved in oncogenesis and tumor progression. Attempts at studying the effects of EWSR1-FLI1 in non-tumor cells to understand the mechanisms underlying sarcomagenesis have been unsuccessful to date, as ectopic expression of EWSR1-FLI1 blocks cell cycle progression and induces apoptosis in the tested cell lines. Therefore, it is essential to find a permissive cell type for EWSR1-FLI1 expression that allows its endogenous molecular functions to be studied. Here we have demonstrated that HeLa cell lines are permissive to EWSR1-FLI1 ectopic expression, and that our model substantially recapitulates the endogenous activity of the EWSR1-FLI1 fusion protein. This model could contribute to better understanding ES sarcomagenesis by helping to understand the molecular mechanisms induced by the EWSR1-FLI1 oncoprotein. [ABSTRACT FROM AUTHOR]