Novel Dual-Pharmacophore TrxR Inhibitors Integrating Ferroptosis and Antitumor Immunity: A Closed-Loop Strategy for TIME Remodeling

Thioredoxin reductase (TrxR) overexpression in tumors is a marker of poor prognosis for liver cancer. Current TrxR inhibitors primarily feature a single pharmacophore. However, dual-pharmacophore TrxR inhibitors have been rarely reported, lacking a clear report on the relationship between their antitumor and potential regulation of tumor immune microenvironment (TIME). Here, we developed a series of dual-pharmacophore TrxR inhibitors via traditional Chinese medicine-ligand synergistic strategy (TLSS). The superior Fa-Au potently inhibited TrxR, suppressed tumor growth, and remodeled TIME by promoting M1 macrophage polarization, DCs maturation, CD8 + T cell activation, and reducing Tregs. Mechanistically, Fa-Au induced oxidative stress and mitochondria-associated ferroptosis via TrxR/GPX4 downregulation, triggering immunogenic cell death (ICD). Therefore, we speculated that Fa-Au induced a novel antitumor immune feedback to stimulate CD8 + T cells and induce ferroptosis through the axis (IFN-γ/STAT1/SLC7A11). This study presents promising applications of dual-pharmacophore TrxR inhibitors as potential chemoimmunotherapeutic agents for cancer treatment.