Reactivation of dysfunctional dendritic cells by a stress-relieving nanosystem resets anti-tumor immune landscape

Dendritic cells (DCs), particularly tumor-infiltrating DCs (TIDCs), are critical to the orchestration of T cell-dependent anti-tumor immune response. However, immunosuppressive tumor microenvironment (TME) conspires to pose multifarious challenges that hinder the function of TIDCs and promote the development of immune evasion. The TIDCs with functional defects usually accumulate excessive lipid, characterized with both aberrantly endoplasmic reticulum (ER) stress and oxidative stress. In this study, we generate a KIRA6 loaded α-Tocopherol nanoemulsion (KT-NE), which concurrently inhibits ER stress sensor inositol-requiring kinase 1α (IRE1α)-X-box binding protein 1 (XBP1) and reactive oxygen species (ROS) in dysfunctional lipid-laden TIDCs. As a result, KT-NE prominently mitigates the XBP1- and ROS-triggered lipid accumulation of TIDCs, which reactivates TIDCs and rehabs their capacity of expanding and stimulating tumor-specific T cells. Moreover, both KT-NE treated TIDCs (adoptive transfer) and KT-NE itself could significantly restore the efficacy of DC-mediated immunotherapy and ease tumor burden in malignant ovarian cancer (OvCa)-bearing mice. In conclusion, co-inhibiting hyperactivated XBP1 and redundant intracellular ROS though KT-NE may be a potent therapeutic strategy to ameliorate the ineffective DCs, reverse hostile TME, evoke robust anti-tumor immunity, and extend host progression-free survival ultimately.