![]() ![]() Advanced 3D models provide the opportunity to reconstruct and comprehend the heterogeneous TME and its dynamic interactions more precisely by using human cells, and tightly regulated cellular compositions, physiological conditions and physical parameters. Therefore, lack of understanding of real-time TME dynamics and identification of cancer specific neoantigen is the major challenge in developing effective immunotherapy. The major challenges posed by CIT approaches include lack of therapeutic responses and acquired resistance. Cancer immunotherapy (CIT) strategies include adoptive T-cell transfer, immune checkpoint inhibitors, monoclonal antibodies, non-specific immune stimulation, oncolytic virus immunotherapy and vaccinations. More recently, immunotherapy has emerged as the preferred regimen because of its ability to induce durable responses, and low degrees of side-effects as compared to other types of treatment methods. Various modes of cancer treatment have been applied in clinic, which include surgery, chemotherapy, hormone therapy, radiation therapy, immunotherapy, targeted therapy, hyperthermia, photodynamic therapy and stem cell transplant. Recent studies have shown that these specialized TME microenvironments and niches have potential to act as target of cancer therapy through reprogramming. Moreover, TME-targeting strategies can be achieved by stimulating the intrinsic host immune system, which encompass either activation of anti-tumor immune cells or inhibiting pro-tumoral immune cells in the TME. Presently, most of the therapeutic efforts involving the TME either focusses on targeting TME components or the development of experimental model systems that accurately mimics complexities of TME. Broadly, six distinct specialized microenvironments within TME have been identified namely the hypoxic niche, acidic niche, innervated niche, metabolism microenvironment, immune microenvironment, and mechanical microenvironment. A dynamic interaction between cancer cells with these cellular and acellular components of TME is essential for generating heterogeneity, clonal evolution and enhancing multi drug resistance in tumor cells. Different factors in the TME unanimously ensure the development, progression and expansion of tumor through an uninterrupted supply of nutrients and oxygen, hampering the immune surveillance reach, and efficient drugs carting. Tumor microenvironment is an ecosystem created by the cancer cells and comprised of components contributed by both tumor and host. Furthermore, a lack of unanimity in defining TME in tumor proximal and distal locations, and unavailability of model systems that accurately mimic the interaction of cancer cells with its microenvironment are the two prime reasons for our limited understanding of TME and exploring its therapeutic potentials. These therapeutic challenges have been exceedingly attributed to the ability of cancer cells to hijack the host machinery to create a niche, i.e., tumor microenvironment for themselves, and progressively modulate it from anti-tumoral to pro-tumoral responses. Even the response to a specific line of therapy varies broadly depending on the type of tumor, i.e., benign, locally advanced or metastatic. However, these approaches are not equally effective across different tumor types and patients. Significant developments made in the field of cancer therapy over the last decade have led to the improvement in the life expectancy of cancer patients. Overall, this review provides a comprehensive account of the current knowledge available to target TME. The later part of the review describes the sophisticated 3D models emerging as valuable means to study TME components and an extensive account of advanced bioinformatic tools to profile TME components and predict neoantigens. The focus of the present review is to understand the complexity of TME and comprehending future perspective of its components as potential therapeutic targets. Therefore, there could be a possibility of reprogramming of TME components to overcome the widely prevailing issue of immunotherapeutic resistance. The variation of TME composition among patients plays an important role in determining responders and non-responders towards cancer immunotherapy. Deeper understanding of the immune cell’s diversity, stromal constituents, repertoire profiling, neoantigen prediction of TMEs has provided the opportunity to explore the spatial and temporal regulation of immune therapeutic interventions. With the advent of 3D culture and advanced bioinformatic methodologies, it is now possible to study TME’s individual components and their interplay at higher resolution. Tumor microenvironment (TME) is a specialized ecosystem of host components, designed by tumor cells for successful development and metastasis of tumor. ![]()
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