Exactly a year ago in our featured article (see Jun/July 2021), we highlighted the importance of IDO-1 interaction with AhR and PD-1 in overcoming immune tolerance within the tumour microenvironment. This has implications for improving the efficacy of future immunotherapies in cancer or at least in ovarian cancer. However, limiting IDO-1 activity may not inhibit kynurenine (KYN) production completely since there are other enzymes, such as TDO-2 that also convert tryptophan to KYN. Further, small-molecule inhibitors via systemic administration can have a short half-life, lack localized effect, and may result in unexpected adverse effects.
To overcome these issues, B. Wang et al. focused on the use of kynureninase (KYNU) instead of IDO-1 as a better immunotherapeutic strategy to overcome immune tolerance within the tumour microenvironment. They demonstrated this using cell-line-derived xenograft mouse models with site-specific hydrogel consisting of KYNU on both breast and melanoma cell lines. They also investigated the synergistic effect of combining KYNU with doxorubicin (Dox), a chemotherapy drug.
They showed that KYNU encapsulated in the hydrogel results in the sustained activity of KYN degradation at the tumour site. This leads to the greatest penetration of immune cells into the tumour microenvironment when used in combination with Dox compared to either a single treatment of KYNU or Dox. This combinatorial therapy can retard tumour growth, induce systemic anti-tumour immunity and limit tumour relapse. It is apparently clear that targeting the kynurenine pathway holds high hopes in cancer treatment.