Embracing cancer immunotherapy with manganese particles

Abstract

A substance integral to the sustenance and functionality of virtually all forms of life is manganese (Mn), classified as an essential trace metal. Its significance lies in its pivotal role in facilitating metabolic processes crucial for survival. Additionally, Mn exerts influence over various biological functions including bone formation and maintenance, as well as regulation within systems governing immunity, nervous signaling, and digestion. Manganese nanoparticles (Mn-NP) stand out as a beacon of promise within the realm of immunotherapy, their focus honed on intricate mechanisms such as triggering immune pathways, igniting inflammasomes, inducing immunogenic cell death (ICD), and sculpting the nuances of the tumor microenvironment. These minuscule marvels have dazzled researchers with their potential in reshaping the landscape of cancer immunotherapy - serving as potent vaccine enhancers, efficient drug couriers, and formidable allies when paired with immune checkpoint inhibitors (ICIs) or cutting-edge photodynamic/photothermal therapies. Herein, we aim to provide a comprehensive review of recent advances in the application of Mn and Mn-NP in the immunotherapy of cancer. We hope that this review will display an insightful view of Mn-NPs and provide guidance for design and application of them in immune-based cancer therapies.

Keywords: Cancer; Drug delivery; Immunotherapy; Manganese; Nanoparticle.

Fig. 1

Mn²⁺ promotes antitumor immune responses. Manganese (Mn) enters the Golgi apparatus and mitochondria of cancer cells. By enhancing the cGAS-STING pathway, Mn promotes dendritic cell maturation and activates cellular immunity, ultimately leading to cancer cell death. Simultaneously, Mn induces the production of reactive oxygen species (ROS) via the GSH pathway, generating hydroxyl radicals (-OH) from hydrogen peroxide (H₂O₂), which further contributes to cancer cell death

Fig. 2

Mn²⁺ promotes DC maturation and antigen presentation and stimulates CD8 + T cell and NK cell activation. Manganese (Mn) induces the maturation of dendritic cells (DCs), enabling them to directly attack cancer cells. Additionally, these DCs activate T cells, leading to cytotoxic T lymphocyte (CTL) infiltration, which subsequently activates natural killer (NK) cells and inhibits regulatory T (Treg) cells. Furthermore, Mn promotes the transformation of M2 macrophages into M1 macrophages, which exhibit robust antitumor immune responses

Fig. 3

The effect MnO₂ and Mn⁺ drug on TME. MnO₂ nanoparticles (NPs) help to change the acidic, hypoxic, and immunosuppressive tumor microenvironment (TME). Under acidic and H₂O₂-rich conditions, MnO₂ does break down in the tumor and releases Mn²⁺ and O₂, which alleviates hypoxia and generates reactive oxygen species (ROS).Mn-NPs can be effective carriers for drugs (e.g. chemotherapy or immunotherapy agents). MnO₂ reacts with tumor acidity / H₂O₂ and decomposes to Mn²⁺ while releasing drugs in a stimuli-responsive manner. It results in drug release specifically and only in the tumor, limiting the off-target effects