Multifunctional Nano Immunostimulant: Overcoming Immunosuppressive Microenvironment for Antitumor Immunotherapy

Abstract Antitumor immunotherapy has become a pillar therapy by activating the immune system to recognize and attack tumor cells. Yet its efficacy is limited by the immunosuppressive tumor microenvironment (TME) and related mechanisms like hypoxia, high glutathione (GSH) expression, and immune evasion. Due to TME complexity and tumor heterogeneity, monotherapy struggles to modulate immunosuppressive factors for potent results. To solve this, this work develops a multifunctional immune stimulator (3IZH), which can simultaneously boost immunity, downregulate GSH, and alleviate hypoxia. In weakly acidic TME, it releases photosensitizer (3ICy5) and Fe ions. Fe ions consume GSH and relieve hypoxia via redox reactions and hydrogen peroxide decomposition. 3ICy5 accumulates in the endoplasmic reticulum (ER), produces ROS, induces severe ER stress and DAMPs release, triggering immunogenic cell death (ICD). Fe ions and ROS also reduce glutathione peroxidase 4 (GPX4), causing ferroptosis. ICD and ferroptosis activate T cell infiltration to restructure TME. Combined with HIF‐1α inhibitor digoxin, 3IZH further reduces HIF‐1α resistance, enhances immune cell infiltration, and shows satisfying efficacy in bilateral tumor‐bearing mice. The regulatory effect of the immune‐suppressive TME, the remarkable therapeutic effect, as well as the safety profile, together indicate the potential of the multifunctional immune stimulator design strategy.