Breakdown of chemo-immune resistance by a TDO2-targeted Pt(IV) prodrug via attenuating endogenous Kyn-AhR-AQP4 metabolic circuity and TLS-promoted genomic instability

[Display omitted] A tryptophan-2,3-dioxygenase 2 (TDO2)-targeted Pt(IV) prodrug, DN604-TDOi, was designed to prove that the multi-action compound could overcome drug resistance and relieve immunosuppression via introducing a TDO2 inhibitor to the axial position of a six-coordinate Pt(IV) hybrid. Several in vitro biological studies on cisplatin-resistant NSCLC cancer cells suggested that TDO2-targeted Pt(IV) prodrug could combat cisplatin resistance via influencing TDO2-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-Aquaporin-4 (AQP4) metabolic circuity and AhR-human DNA polymerase (hpol) κ-induced translesion DNA synthesis (TLS) genomic instability, which are positive in drug-resistant human tumors associated with malignant progression and poor survival. Remarkably, we observed that DN604-TDOi could inhibit TDO2-mediated constitutive Kyn-AhR-AQP4 signaling pathway and suppress hpol κ expression, leading to potential decrease of cell motility and genomic instability in A549/cDDP cells. It was confirmed that TDO2-targeted Pt(IV) prodrug could harness Kyn-AhR-AQP4 metabolic circuitry and TLS genomic instability, exerting antitumor effects in C57BL6 but not TDO2-/- mice. Moreover, the Pt(IV) prodrug improved the intratumoral infiltration of Teff cells and reduced the recruitment of Treg cells. The results provided compelling preclinical evidence that TDO2-targeted Pt(IV) prodrug could abrogate immune chemotherapeutic resistance via decaying TDO2-mediated Kyn-AhR-AQP4 immunosuppression and AhR-hpol κ-induced TLS genomic instability, underscoring the development of a novel Pt(IV)-based candidate as a potent immunotherapeutic agent for chemo-immune resistance prevention.