Gallium Nanoparticles‐Mediated Metalloimmunotherapy Overcomes Immunological Tolerance Induced by Ferroptosis

ABSTRACT As a typical immunogenic cell death, ferroptosis plays a vital role in inducing an immune‐active tumor microenvironment. But, how to induce effective tumor ferroptosis without causing innate and acquired immune‐resistance is still a difficult issue to solve. Here, we develop a hydrogen peroxide‐sensitive gallium‐releasing nanoparticle (Ga@MnO 2 @Alb) by bio‐mineralization and positive and negative electric adsorption methods. Apart from serving as a novel ferroptosis inducer, gallium (Ga) released from Ga@MnO 2 @Alb also avoids the occurrence of innate and acquired immune‐resistance of traditional ferroptosis inducers by depressing cluster of differentiation 47 (CD47) and programmed death ligand 1 (PD‐L1) expression through influencing mitochondria/Adenosine 5’‐monophosphate‐activated protein kinase (AMPK)/c‐MYC axis. By doing this, the depression of “don't eat me” innate immune signal CD47 and “don't find me” adoptive immune signal PD‐L1 strengthen T cell killing capacity and macrophage phagocytosis ability to tumor cells. Moreover, Ga@MnO 2 @Alb alone or in combination therapy with radiotherapy increases the infiltration of T cells in tumors, slows the process of tumor metastasis, and inhibits the local and abscopal tumor growth. All in all, our research reveals the negative immune regulation phenomenon of ferroptosis, indicating the potential of using Ga@MnO 2 @Alb‐mediated metalloimmunotherapy as a more effective ferroptosis‐inducing strategy with self‐immune checkpoint regulation capacity.