Although the antitumor efficacy of
immune checkpoint blockade (ICB) has been proved in
colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of
tryptophan metabolism
enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and
tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that
sodium tanshinone IIA sulfonate (STS), a sulfonate derived from
tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for
natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased
kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed
tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma
kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in
tumors. Flow cytometry analysis of immune cells in
tumor tissues demonstrated an increase in the percentage of
tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an
immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.