Fig. 4: The value of EVs in the radiotherapy-mediated TME.
From: Radiotherapy remodels the tumor microenvironment for enhancing immunotherapeutic sensitivity
The IFN-I pathway in tumor cells is activated by irradiation, and tumor cells release EVs carrying dsDNA. These EVs stimulate the expression of co-stimulatory molecules CD80 and CD86 and activate the cGAS/STING pathway in DCs to secrete IFN-β. RT promotes the release of exosomes from tumor cells to activate DCs, which contain HMGB1, CRT and HSP70. Similarly, irradiated tumors upregulate HSP70, HSP90 and a potential TAA, CDCP1 protein, in EVs. DCs have an enhanced ability to phagocytose EVs and perform antigen presentation, thereby activating CD8+ T cells via the PI3K/Akt signaling pathway. In addition, irradiated tumor cell-derived EVs activate Aim2 inflammasome in macrophages and induce IL-1β production to stimulate DCs. Contact of EVs carrying HMGB1 with TAMs results in increased expression of activation markers CD86, CD64, CCR7 and pro-inflammatory factors TNF-α and IL-12 p70, suggesting a conversion of M2 to M1 macrophages. Solid lines represent anti-tumor effects and dashed lines represent pro-tumor effects.
