Novel tryptophan 2,3-dioxygenase-targeted ruthenium(ii)-indole complex activates immunotherapy

Immunotherapy targeting immune checkpoints has emerged as a promising strategy in cancer treatment; however, the heterogeneous and dynamic tumor microenvironment (TME) imposes critical constraints on therapeutic outcomes. Tryptophan 2,3-dioxygenase (TDO), often dysregulated in malignant tissues, plays a pivotal role in shaping an immunosuppressive milieu by depleting tryptophan, thereby hindering anti-tumor immune response. To counteract this immune evasion mechanism, we designed a novel indole-coordinated ruthenium(ii) arene complex (In-Ru), aimed at bolstering tumor immunotherapy and thwarting immune evasion by targeting TDO expression. Our findings reveal that In-Ru exerts markedly potent anti-proliferative effects against HepG2 cells. It achieves this by specifically localizing to the cell nucleus, inducing DNA damage, and initiating a cascade of necroptosis as well as immunogenic cell death (ICD), thereby potentially enhancing the immune system's capacity to recognize and attack cancer cells. RNA sequencing and qRT-PCR analysis indicate that In-Ru modulates pathways linked to tryptophan metabolism and immune reprogramming, with specific degradation of TDO protein and reversal of tryptophan-mediated immunosuppression. Furthermore, TDO inhibition boosts ROS production and induces necroptosis