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. 2023 Feb 4;10(5):1809–1811. doi: 10.1016/j.gendis.2023.01.001

Figure 1.

Fig. 1

NU7441 promotes anti-tumoral immunity via triggering cytosolic DNA sensing and inducing an inflamed TME in metastatic triple-negative breast cancer (TNBC). (A) Gene Set Enrichment Analysis (GSEA) showed that Toll-like receptor signaling, NOD-like signaling, and cytosolic DNA-sensing were up-regulated by NU7441. In GESA cytosolic DNA sensing, STING, RIG-I, IRF7, NFkB, and PolR3G were up-regulated. (B) Western blot showed cGAS, STING, RIG-I, MAVS, and P–P65 levels were up-regulated by NU7441 in BT549 cells. (C) In Balb/c mice subcutaneously injected with NU7441(70 mg/kg total dose), ELISA results showed the serum IFN-β was increased by NU7441. (D) NU7441 was intraperitoneally injected into the immune-competent xenograft Balb/c mice bearing 4T1 TNBC cells (100 mg/kg total dose). NU7441 suppressed the tumor growth in immune-competent xenograft Balb/c mice through tumor volume calculation. (E) NU7441 was intraperitoneally injected into athymic nude xenograft Balb/c mice (100 mg/kg total dose). NU7441 did not suppress the tumor growth in athymic nude xenograft mice through tumor volume calculation. (F) The HE staining results showed NU7441 suppressed the TNBC metastasis to the lungs in immune-competent xenograft Balb/c mice but not in athymic nude xenograft mice. (G) NU7441 inhibited tumor metastasis to lungs in immune-competent xenograft mice but had no effects on tumor metastasis in athymic nude xenograft mice through counting tumor nodules. (H) NU7441 increased the infiltrations of CD45+ cells, CD4+ and CD8+ T cells, and CD1a+ antigen-presenting cells in TME in immune-competent Balb/c xenograft mice bearing 4T1 cells through flow cytometry analysis. (I) Immunohistochemistry results showed that NU7441 increased the IFNAR and MHC-I levels in TME in immune-competent xenograft mice. In the TME of athymic nude mice, there is no observable IFNAR expression shown up in immunohistochemistry staining, and MHC-I levels were not altered by NU7441. (J) A diagram exhibiting the roles of DNA-PKcs in cytosolic DNA sensing, inflamed TME, and anti-tumoral immunity. Targeting DNA-PKcs promotes anti-tumoral immunity via triggering cytosolic DNA sensing, inducing an inflammation TME, and recruiting lymphocytes in metastatic TNBC.