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Simple Summary: As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, extracellular matrix (ECM), and soluble molecules forming the widely recognized tumor microenvironment. The main components of the tumor microenvironment include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), ECM, and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). The tumor microenvironment has been suggested to play a central role in tumor progression and treatment resistance. Accumulated evidence indicates that tumor maintenance, progression, and treatment resistance are determined by components of the microenvironment. Thus, targeting the components of the tumor microenvironment may have a therapeutic impact on melanoma treatment. The main topic of this paper deals with the main components of the tumor microenvironment and their impact as therapeutic targets in melanoma treatment. The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer in the head and neck region (HNSCC) is exponentially increasing due to human papillomavirus (HPV) infections. This paper helps us to understand the complexity of the inflammatory networks and the mechanisms of immune evasion in HPV+ HNSCC to open up new avenues and drive the discovery of useful tools to be translated clinically in the screening and treatment of these cases, especially to overcome resistance and improve patients' quality of life. Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignancies which have shown exponential incidence in the last two decades especially due to human papillomavirus (HPV) infection. The HPV family comprises more than 100 types of viruses with HPV16 and HPV18 being the most prevalent strains in HNSCC. Literature data reveal that the mutation profile as well as the response to chemotherapy and radiotherapy are distinct among HPV+ versus HPV-negative tumors. Furthermore, the presence of the virus induces activation of an immune response, in particular the recruitment of specific antiviral T lymphocytes to tumor sites. These T cells when activated produce soluble factors including cytokines and chemokines capable of modifying the local immune tumor microenvironment and impact on tumor response to the treatment. In this comprehensive review we investigated current knowledge on how the presence of an HPV can modify the inflammatory response systemically and within the tumor microenvironment's immunological responses, thereby impacting on disease prognosis and survival. We highlighted the research gaps and emerging approaches necessary to discover novel immunotherapeutic targets for HPV-associated HNSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteosarcoma is the most common primary bone tumor and has a poor prognosis. Therefore, it is important to understand the mechanism of the development of osteosarcoma to overcome therapy resistance. Several mathematical models have been developed to study the initiation and progression of many cancer types. However, there are currently no mathematical models for the progression of osteosarcoma, to the best of our knowledge. In this work, we develop a data-driven mathematical model to analyze the impact of the immune cell interactions on the growth of osteosarcoma tumors that have distinct immune patterns. Our model provides a foundation for investigating the effect of various treatments on the dynamics of key players in the primary tumor, including immune cells and cytokines, and ultimately the whole tumor. As the immune system has a significant role in tumor progression, in this paper, we develop a data-driven mathematical model to study the interactions between immune cells and the osteosarcoma microenvironment. Osteosarcoma tumors are divided into three clusters based on their relative abundance of immune cells as estimated from their gene expression profiles. We then analyze the tumor progression and effects of the immune system on cancer growth in each cluster. Cluster 3, which had approximately the same number of naive and M2 macrophages, had the slowest tumor growth, and cluster 2, with the highest population of naive macrophages, had the highest cancer population at the steady states. We also found that the fastest growth of cancer occurred when the anti-tumor immune cells and cytokines, including dendritic cells, helper T cells, cytotoxic cells, and IFN- γ , switched from increasing to decreasing, while the dynamics of regulatory T cells switched from decreasing to increasing. Importantly, the most impactful immune parameters on the number of cancer and total cells were the activation and decay rates of the macrophages and regulatory T cells for all clusters. This work presents the first osteosarcoma progression model, which can be later extended to investigate the effectiveness of various osteosarcoma treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy, and it has greatly expanded our knowledge of anticancer immunity and has introduced breakthroughs in cancer therapy. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. This review provides an overview of recent advances in cellular and molecular factors within the tumor microenvironment (TME) to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies for cancer immunotherapy. The in-depth exploration of complexity within the TME allows for the improvement of therapeutic efficacy and highlights its contribution to cancer immunotherapy. Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review paper here describes the recent progress that has been made in chimeric antigen receptor (CAR) -based therapies for treatment of tumors and the role of metabolism in the tumor microenvironment in relation to these therapies. Moreover, this manuscript also discusses role of different CAR-based cells for treatment of solid tumors, which is a major challenge in the CAR immunotherapy field. Chimeric antigen receptor (CAR) T cell-based therapies have shown tremendous advancement in clinical and pre-clinical studies for the treatment of hematological malignancies, such as the refractory of pre-B cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and large B cell lymphoma (LBCL). However, CAR T cell therapy for solid tumors has not been successful clinically. Although, some research efforts, such as combining CARs with immune checkpoint inhibitor-based therapy, have been used to expand the application of CAR T cells for the treatment of solid tumors. Importantly, further understanding of the coordination of nutrient and energy supplies needed for CAR T cell expansion and function, especially in the tumor microenvironment (TME), is greatly needed. In addition to CAR T cells, there is great interest in utilizing other types of CAR immune cells, such as CAR NK and CAR macrophages that can infiltrate solid tumors. However, the metabolic competition in the TME between cancer cells and immune cells remains a challenge. Bioengineering technologies, such as metabolic engineering, can make a substantial contribution when developing CAR cells to have an ability to overcome nutrient-paucity in the solid TME. This review introduces technologies that have been used to generate metabolically fit CAR-immune cells as a treatment for hematological malignancies and solid tumors, and briefly discusses the challenges to treat solid tumors with CAR-immune cells. [ABSTRACT FROM AUTHOR]