Edited by Yi-Ching Wang
A thematic series in Journal of Biomedical Science.
The past decade has been a revolution in understanding about interactions between supporting cells creating tumor microenvironment (TME) with cancer cells. TME is the cellular environment in which the tumor exists, including surrounding blood/lymphatic vessels, immune cells, fibroblasts, signaling molecules, cytokines and the extracellular matrix. The TME is actually a special niche for innutrition, acidity, and hypoxia. Stromal cells, cancer cells, and infiltrating immune cells secrete a high array of growth factors and cytokines to the TME. These secretions provide autocrine and more potently paracrine interactions within the TME. Moreover, epigenetic regulation may similarly affect the cancer cells and architecture of the TME. Recently, various detective techniques and genome-wide profiling provided an unprecedented view of the composition, function and location of various stromal cells within the TME.
In the present thematic series, we have provided evidence to define classes of TME and determine which cells, molecules and pathways are essential for fostering TME or suppressing antitumor immunity, and in what tumor contexts. Kuo et al. describe critical structure and regulation in vesicular secretion-involved interplays between tumor cells, stromal cell and host immunity. New insights into the role of the conventional protein secretion and unconventional secretions through extracellular vesicles and autophagosomes under normal physiological conditions and cancers are summarized. As to the impact of reactive oxygen species (ROS) in the TME, Kuo, Ponneri Babuharisankar et al. discuss the combination of emerging ROS-modulating strategies with immunotherapies to achieve antitumor effects. They also side-by-side lay out the molecular, cellular, and system events to highlight the current status of both "friend" and "foe" of mitochondrial ROS in cancer. Tiwari et al. present multiple aspects of targeting the TME for effective therapy and cancer immunotherapy resistance. Notably, various cell/extracellular matrix‑based 3D models and bioinformatics tools to assess tumor purity, compute cell proportions, and identify specific cell-type subsets in TME are systematically reviewed. In the past few years, research in the TME has been accelerated dramatically by the development of multiplexed spatial multi-omic technology, which has expanded the landscape of TME as well as our understanding of its regulation. Hsieh et al. review the principles and techniques of the recent high-resolution methods such as single-cell RNA sequencing, flow cytometry and imaging. In addition, Li & Hung describe current advances and controversies in understanding the reprogramming of TME in tumor-draining sentinel lymph node as the nucleating point for distant cancer metastasis. The impact of immunotherapy on sentinel lymph node is discussed. Chen et al. evaluate in their review the interplay between cancer-associated fibroblasts, tumor cells and immune cells in relation to how they shape the TME and the host response to immune checkpoint blockade. Finally, Tien, Lu, Lin et al. focus on an attractive topic, the interplay between epigenetic modulators and immunomodulators, which is a growing interest in the fields of cancer epigenetics and immunology. This work casts key sections in DNA methylation and histone modification enzymes in immune cells and the tumor-immune interface (immune synapse); and epigenetic therapy for modulation of TME. Current advances in epigenetic drugs and mechanisms that lead to a series of discoveries on cancer-specific neoantigen as well as immunologic cellular plasticity and epigenetic molecular plasticity are nurturing those new in the TME to follow.
Due to the broad nature of components and their regulation in the TME, it is not our intention to cover all major aspects of this active research area in this single issue. However, we hope that these articles provide readers of the Journal of Biomedical Science with insightful information of how alterations of vesicular secretion, oxidation environment, lymphogenesis, fibrosis and epigenetic regulations may be used as disease biomarkers and for designing therapies targeting TME.