Secreted factors such as leukotriene B4 (breast cancer), glioma cell-derived placental growth factor (glioma), TNF-α (tumor cells), and IL-21 (T cells), as well as cell contact-dependent mechanisms (CD40-CD40L and PD-1-PD-L1 axis,), promote cell differentiation Bregs in the TME [78,79,80,81,82,83]. Here, CD40LG is linked to central nervous system cancer.