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**shIDO-ST** is an engineered attenuated *Salmonella typhimurium* (VNP20009 strain) bacterial vector designed for cancer immunotherapy. It carries a plasmid expressing short hairpin RNA (shRNA) that specifically silences **indoleamine 2,3-dioxygenase (IDO)**, an immunosuppressive enzyme overexpressed in tumors that depletes tryptophan and promotes immune evasion. Administered systemically (intravenous or intraperitoneal), shIDO-ST preferentially colonizes hypoxic tumor microenvironments, locally reducing IDO expression and activity, which triggers robust innate immune activation including neutrophil influx, reactive oxygen species production, and tumor cell death independent of adaptive immunity or host IDO. Preclinical studies in immunocompetent mouse models of colorectal cancer (CT26, MC38), pancreatic cancer, and melanoma demonstrate superior tumor growth delay compared to small-molecule IDO inhibitors like epacadostat or anti-PD-1 monotherapy, with enhanced effects in combinations such as PEGPH20 or anti-PD-1/CTLA-4.[2][4][11]
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