Cancer Genetics and Epigenetics, 2025, Vol.13, No.2, 62-76 http://medscipublisher.com/index.php/cge 67 5.4 Signal transduction pathways The signal transduction pathway plays a key role in regulating various life activities such as cell proliferation, differentiation and survival. In EAC, scientists discovered a transcriptional feedback loop involving the master regulatory transcription factor (mrtf) and the nuclear receptor PPARG. This cycle links the imbalance of "acquired alterations" in genes with changes in cellular metabolism, promoting the progression of EAC. Blocking this feedback loop might become a new approach to treating EAC (Ma et al., 2021). Furthermore, systems biology studies have shown that the TGFB and JNK signaling pathways in EAC are overly active, and these two pathways regulate genes related to tumor growth and deterioration (Blum et al., 2019). These research results all emphasize the importance of the signal transduction pathway in the pathogenesis of EAC. 6 Tumor Microenvironment and Immune Evasion 6.1 Communication between tumor cells and the surrounding environment Esophageal adenocarcinoma (EAC) forms in a complex peri-tumor environment (TME), gradually evolving from Barrett's esophagus (BE) to adenocarcinoma at different abnormal stages. The TME characteristic of EAC is the close communication between tumor cells and various immune cells. Studies have found that when the disease progresses from normal esophagus to adenocarcinoma, the number of FOXP3+ T regulatory cells and CD163+ bone marrow monocytes continues to increase (Sundaram et al., 2022). In addition, a new type of CSF1R+CD1C+ myeloid cell was discovered. The number of this cell increased in the more advanced stage of the disease, showing the complexity and dynamic changes of the immune environment (Sundaram et al., 2022). 6.2 Methods for EAC to evade the immune system EAC tumors use multiple ways to evade the detection of the immune system. An important approach is to reduce the number of major histocompatibility complex Class I (MHC1) proteins, which was observed in 32% of EAC patients. The result makes it more difficult for T cells to detect tumor cells (Schoemmel et al., 2021). Another approach involves the production of immune checkpoint proteins (such as PD-L1), which increases in EAC, creating an immune-suppressing environment and "braking" T cell activity (Lagisetty et al., 2020). Moreover, the immune environment of EAC is usually characterized by the entry of fewer effector cells capable of killing tumors and an increase in immune inhibitory signals, such as elevated PD-L1 and the deletion of CD8+T cells (Lagisetty et al., 2020). These methods jointly caused the phenomenon of immune evasion observed in EAC. 6.3 Potential markers of immune response Finding the indicators that can predict the immunotherapy effect of esophageal adenocarcinoma (EAC) is crucial for the development of effective immunotherapy. Studies have shown that patients with a large number of CD8+ tumor-infiltrating lymphocytes (TIL) in tumors have a better therapeutic effect with immune checkpoint inhibitors, indicating that CD8+ TIL can be used to determine whether the treatment is effective (Li et al., 2019). Furthermore, the study also found that the expression levels of immune checkpoint indicators such as LAG3, TIM3, CTLA4 and CD276 were relatively high in patients with EAC, which means they can be used in combined immunotherapy regimens (Wagner-ryczek et al., 2020). In some patients with gastroesophageal adenocarcinoma (GEA), tertiary lymphoid structures (TLSs) have been found. Since this structure is associated with a strong immune response, it is likely to become an important target for immunotherapy (Figure 2) (Derks et al., 2020). The environment around EAC tumors is very complex, involving the mutual influence of multiple immune cells, and the tumors will also use various methods to evade immune attacks. Understanding these changes and finding reliable indicators is an important step in improving the immunotherapy methods for EAC. The research of Derks et al. (2020) has helped us understand the indicators related to immune response in EAC, especially in different tumor environments. Identifying these indicators is crucial for developing effective immunotherapies, especially in determining whether patients respond to immune checkpoint inhibitor treatment. As can be seen from Figure 2, there are significant differences in certain immune indicators among patients with different types of EAC, which means that personalized treatment plans can be formulated based on the specific conditions of the patients.
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