The tumor microenvironment plays a critical role in PD-L1/PD-1-mediated tumor immune escape. PD-L1/PD-1 signaling is a key component of tumor immunosuppression, inhibiting T-cell activation and enhancing tumor immune tolerance, thereby enabling tumor immune evasion. Targeting this pathway is an attractive strategy for cancer treatment, but its therapeutic effectiveness remains limited. Understanding the complex molecular mechanisms and factors driving PD-L1/PD-1 expression and activation in the tumor microenvironment is essential for improving treatment outcomes. The tumor microenvironment consists of various non-transformed cells, including stromal cells, fibroblasts, immune cells, and vascular endothelial cells, along with a complex network of signaling molecules. These components interact to regulate tumor growth, metastasis, and immune evasion. Inflammatory factors, cytokines, and exosomes in the tumor microenvironment can induce PD-L1 expression, promoting immune escape. PD-L1 is widely expressed in tumor cells and non-blood cells, and its expression is influenced by various factors, including cytokines, exosomes, and non-coding RNAs. PD-1 is a type I transmembrane protein that inhibits T-cell activation and promotes apoptosis. PD-L1 is a ligand of PD-1 and is involved in immune checkpoint regulation. The PD-L1/PD-1 pathway is regulated by various signaling pathways, including JAK/STAT, PI3K-AKT, and NF-κB. Inflammatory factors such as IFN-γ, TNF-α, and IL-6 can induce PD-L1 expression, enhancing immune evasion. Growth factors like EGF, TGF-β, and GM-CSF also contribute to PD-L1 expression and tumor immune escape. Non-coding RNAs, including lncRNAs and miRNAs, play a significant role in regulating PD-L1 expression. For example, miR-513 and miR-155 can inhibit PD-L1 expression by targeting its mRNA, while circRNAs can act as miRNA sponges to enhance PD-L1 expression. These regulatory mechanisms highlight the complexity of PD-L1/PD-1 signaling in the tumor microenvironment. Despite the importance of PD-L1/PD-1 in tumor immune escape, the therapeutic response to PD-L1/PD-1 inhibitors remains limited, particularly in solid tumors. This is attributed to factors such as tumor heterogeneity, individual differences, and the complex tumor microenvironment. Further research is needed to understand the mechanisms of PD-L1/PD-1 regulation in the tumor microenvironment and to develop more effective immunotherapies for cancer patients.The tumor microenvironment plays a critical role in PD-L1/PD-1-mediated tumor immune escape. PD-L1/PD-1 signaling is a key component of tumor immunosuppression, inhibiting T-cell activation and enhancing tumor immune tolerance, thereby enabling tumor immune evasion. Targeting this pathway is an attractive strategy for cancer treatment, but its therapeutic effectiveness remains limited. Understanding the complex molecular mechanisms and factors driving PD-L1/PD-1 expression and activation in the tumor microenvironment is essential for improving treatment outcomes. The tumor microenvironment consists of various non-transformed cells, including stromal cells, fibroblasts, immune cells, and vascular endothelial cells, along with a complex network of signaling molecules. These components interact to regulate tumor growth, metastasis, and immune evasion. Inflammatory factors, cytokines, and exosomes in the tumor microenvironment can induce PD-L1 expression, promoting immune escape. PD-L1 is widely expressed in tumor cells and non-blood cells, and its expression is influenced by various factors, including cytokines, exosomes, and non-coding RNAs. PD-1 is a type I transmembrane protein that inhibits T-cell activation and promotes apoptosis. PD-L1 is a ligand of PD-1 and is involved in immune checkpoint regulation. The PD-L1/PD-1 pathway is regulated by various signaling pathways, including JAK/STAT, PI3K-AKT, and NF-κB. Inflammatory factors such as IFN-γ, TNF-α, and IL-6 can induce PD-L1 expression, enhancing immune evasion. Growth factors like EGF, TGF-β, and GM-CSF also contribute to PD-L1 expression and tumor immune escape. Non-coding RNAs, including lncRNAs and miRNAs, play a significant role in regulating PD-L1 expression. For example, miR-513 and miR-155 can inhibit PD-L1 expression by targeting its mRNA, while circRNAs can act as miRNA sponges to enhance PD-L1 expression. These regulatory mechanisms highlight the complexity of PD-L1/PD-1 signaling in the tumor microenvironment. Despite the importance of PD-L1/PD-1 in tumor immune escape, the therapeutic response to PD-L1/PD-1 inhibitors remains limited, particularly in solid tumors. This is attributed to factors such as tumor heterogeneity, individual differences, and the complex tumor microenvironment. Further research is needed to understand the mechanisms of PD-L1/PD-1 regulation in the tumor microenvironment and to develop more effective immunotherapies for cancer patients.