# Tumor Microenvironment and Dermatological Conditions in Prostate Cancer
### Mechanisms of PCa Progression
In recent years, different cells and molecules influenced or stimulated by the TME have been found to impact tumor survival. The metabolic complexity and plasticity of the TME facilitate cancer cells to establish an invasive phenotype. One of the main characteristics of the TME in PCa is the very low or even absent number of T lymphocytes that exhibit antitumor activity in association with an increased number of macrophages. Therefore, macrophages can account for up to 50% of the inflammatory cells found in the TME. A recent study focused on the analysis of the role of Yin Yang 1, a transcription factor, in the pathogenesis of PCa. It has been observed that M2 macrophages expressing this factor in increased amounts contribute to the progression of PCa by promoting IL6 overexpression [25]. Tumor-associated M2 macrophages promote growth and induce immunosuppression. Macrophages could also be crucial in metastatic disease, as a recent study involving patients with metastases treated with docetaxel revealed elevated levels of cytokines linked to macrophages in the blood of these patients. Consequently, in prostate cancer, macrophages seem to play a major role in promoting the development and progression of the disease [26]. CD47 is overexpressed in PCa, where it helps cancer cells evade immune detection by preventing macrophages from phagocytosing them. A recent study found that blocking CD47 enhances macrophage phagocytosis of tumor cells, suggesting that CD47 plays a key role in the tumor's immune microenvironment. As a result, CD47 may serve as a promising target for developing new immunotherapy strategies for PCa [27]. An important role is also played by cancer-associated fibroblasts, which are activated by various mediators, and in turn release a series of cytokines and extracellular matrix (ECM) proteins. The released mediators exhibit a chemoattractant effect and thus infiltrating lymphocytes including NKT, NK, or T cells will migrate to the tumor site and release antiproliferative factors resulting in the activation of apoptosis mechanisms with the final result of tumor death. At the same time, the released cytokines activate immune cells that will produce ECM remodeling factors with consequences on the tissue architecture and its vascularization and tumor progression will be promoted (Figure 1) [28]. Many exosomes produced by mesenchymal cells increase the migration of cancer cells. Moreover, cancer-associated fibroblasts and the ECM are important players in cancer cell migration and tumor progression and can also impact the therapeutic outcome. In the tumor microenvironment, numerous interactions take place between cells and structural elements, interactions that promote the aggressive behavior and the dissemination of malignant cells that contribute to hypoxia, and promote the development of lesions in distant locations [18]. Immunosuppressive neutrophils are a group of myeloid cells that are associated with tumor proliferation and poor response to therapy. It has been shown that immunosuppressive neutrophils in the TME exhibit markers of senescence on the surface. Apolipoprotein E secreted by tumor cells promotes senescence into neutrophils expressing triggering receptor expressed on myeloid cells 2 (TREM2). These cells have been shown to induce a stronger immunosuppressive effect compared to classic immunosuppressive neutrophils. The presence of TREM2+ neutrophils in the TME correlates with an unfavorable outcome [29]. The subset of immune cells predominant in the TME decisively influences the immune response and the antitumor response through the cytokines and chemokines they release. Thus, Tregs acting as immunosuppressive promote tumor progression and have been associated with a low survival rate. On the other hand, an increased number of CD8 T cells, or cytotoxic T lymphocytes, was associated with a favorable outcome of the disease. As for the activity of B lymphocytes, this depends on the immune cells and mediators released into the TME.