VNP2000 9, a genetically modified strain of Salmonella typhii?Wrium with deletions in the msbB and purl loci, exhibited antitumor activities when given systemically to tumor-bearing mice. VNP2000 9 inhibited the growth of subcutaneously implanted B16F10 murine melanoma, and the human tumor xenografts Lox, DLD-1, A549, WiDr, HTB177, and MDA MB-231. A single intravenous injection of VNP20009 , at doses ranging from 1 x Hf to 3 x 106 cfulrnouse, produced tumor growth inhibitions of 57-95%. Tumor volume doubling time, another indicator for tumor growth inhibition, also significantly increased in mice treated with VNP2000 9. Using mice with immune system deficiencies, we also demon• strated that the antitumor effects of VNP20009 did not depend on the presence ofT and B cells. In addition, VNP20009 , given intravenously, inhibited the growth of lung metastases in mice. Only live bacteria showed the antitumor effect.

Glioblastoma (GBM) is the deadliest form of brain cancer, characterized as a highly angiogenetic and immunosuppressive malignancy. Although immune checkpoint blockades have revolutionized cancer therapy, their therapeutic efficacy in GBM has been far less than expected or even ineffective. Here, we reveal that the genomic signature of glioma-derived endothelial cells (GdECs) correlates with an immunosuppressive state and poor prognosis of glioma patients. In vitro model of GdECs differentiation is established for drug screening, and we identify that cAMP activators could effectively block the GdECs formation by inducing oxidative stress. cAMP activator impairs the GdECs differentiation in vivo, normalizes the tumor vessels, and alters the immune profile, especially increasing the influx and function of CD8+ effector T cells. The dual blockade of GdECs and PD-1 induces tumor regression and establishes anti-tumor immune memory. Our study reveals that endothelial transdifferentiation of GBM shapes an endothelial immune cell barrier and supports the clinical development of combining GdECs blockade and immunotherapy for GBM.