Fig. 5: The main mechanisms of therapy targeting TME in SMARCA4-UT.

Tumor-associated antigens (TAAs), those released by tumor cells killed by radiation, are presented to immune cells, and activated CD8⁺ Teffs are recruited to the tumor and release IFN-γ. The level of PD-1 on CD8⁺ Teffs and PD-L1 on tumor cells are increased, and tumor cells can be killed accompanied by enhanced response of PD-1 inhibitors. VEGF inhibits DCs maturation and the activation and infiltration of Teffs, while upregulating the activity of MDSCs and Tregs. OVs selectively kill cancer cells, thereby releasing TAAs, PAMPs and DAMPs to activate APCs. OVs promote the production of IFN and T cell-recruiting chemokines to recruit Teffs into the tumor, and induce PD-L1 expression on tumor cells and MHC I expression. Furthermore, oncolytic virotherapy decreases immunosuppressive cells, and reduces VEGF levels in TME. EZH2 inhibitor promotes the growth, differentiation and activation of NK cells, and promotes the secretion of CXCL9 and CXCL10 to recruit NK cells, M1 TAMs, and CD4⁺ and CD8⁺ Teffs to the tumor, thereby killing tumor cells. EZH2 inhibitor upregulates the expression of MHC I and MHC II and increases the expression of PD-L1 on tumor cells and PD-1 on CD8⁺ Teffs. Furthermore, EZH2 inhibitor decreases Tregs infiltration and inhibits VEGF-A/AKT signaling pathway.(Created with BioRender.com).