Fig. 6

Cellular and molecular mechanisms of immune imbalance in TETs immunotherapy. A. PD-1/PD-L1 interaction in the thymic tissue regulates T cell development, and antigen-activated T cells upregulate PD-1 to avoid overactivation mediated tissue attack. B. Activated T cells release IFN-γ which upregulate PD-L1 expression in tumor cells via ERK/JAK2-STAT signaling pathways. Additionally, some circRNAs expressed by tumor cells may be involved in regulation of immune imbalance in TETs. C. Some lncRNAs, LncXLOC_003810, for example, can inhibit PD-1/PD-L1signaling and may be involved in regulating T cell differentiation. PD-1/PD-L1 signaling can inhibit PI3K/AKT pathway, which, however, can be activated by some immune related miRNAs. D. The immune microenvironment in TETs is distorted. PD-1/PD-L1 and their directly or indirectly interacting molecules play a vital role in maintaining immune homeostasis either inside or outside the thymus. However, this balance is disrupted in TETs especially after immunotherapy, which make TETs susceptible to irAEs during immunotherapy. TCR: T cell receptor; SHP2: Src homology 2 domain-containing tyrosine phosphatase 2; irAEs: Immune-related adverse events; ICIs: Immune checkpoint inhibitors; TETs: Thymic epithelial tumors