Manganese‐Based Tumor Immunotherapy

Abstract

As an essential micronutrient, manganese (Mn) participates in various physiological processes and plays important roles in host immune system, hematopoiesis, endocrine function, and oxidative stress regulation. Mn‐based nanoparticles are considered to be biocompatible and show versatile applications in nanomedicine, in particular utilized in tumor immunotherapy in the following ways: 1) acting as a biocompatible nanocarrier to deliver immunotherapeutic agents for tumor immunotherapy; 2) serving as an adjuvant to regulate tumor immune microenvironment and enhance immunotherapy; 3) activating host's immune system through the cGAS‐STING pathway to trigger tumor immunotherapy; 4) real‐time monitoring tumor immunotherapy effect by magnetic resonance imaging (MRI) since Mn2+ ions are ideal MRI contrast agent which can significantly enhance the T1‐weighted MRI signal after binding to proteins. This comprehensive review focuses on the most recent progress of Mn‐based nanoplatforms in tumor immunotherapy. The characteristics of Mn are first discussed to guide the design of Mn‐based multifunctional nanoplatforms. Then the biomedical applications of Mn‐based nanoplatforms, including immunotherapy alone, immunotherapy‐involved multimodal synergistic therapy, and imaging‐guided immunotherapy are discussed in detail. Finally, the challenges and future developments of Mn‐based tumor immunotherapy are highlighted.

Orchestrated Cytosolic Delivery of Antigen and Adjuvant by Manganese Ion-Coordinated Nanovaccine for Enhanced Cancer Immunotherapy

“…Over the past few decades, studies have shown that metal ions such as Zn 2+ , Ca 2+ , and Mn 2+ etc. play important roles in the activation of innate or adaptive immunity. , Diverse small molecules including metal ions have been developed as immunostimulatory adjuvants to augment antigen immunogenicity. − In particular, Mn 2+ has been demonstrated to activate the cyclic GMP-AMP synthase (cGAS) and stimulator interferon gene (STING) pathway and is able to synergize with immune checkpoint inhibitors for cancer immunotherapy. , However, unfavorable pharmacokinetics and possible neurotoxicity of Mn 2+ limited its wide applications in cancer immunotherapy . To improve the efficacy, various nanoparticle-based formulations have been developed to improve the immune activation effect of Mn 2+ . − The formulation of Mn 2+ with antigens into a subunit cancer nanovaccine may be advantageous for spatiotemporal codelivery of the subunit antigens and Mn 2+ to the cytoplasm, where they may achieve orchestrated immune responses in the subcellular compartment.…”

Advances of MnO2 nanomaterials as novel agonists for the development of cGAS-STING-mediated therapeutics

“…It has been widely reported that there is excessive GSH in the tumor microenvironment, which provides sufficient reductant for the reduction of MnO 2 ( 88 ). Under acidic conditions, GSH is oxidized to glutathione disulfide (GSSG) through mercaptan disulfide exchange, while MnO 2 is reduced to Mn 2+ ( 89 ). The reaction formula during the reaction between MnO 2 and GSH are as shown as following:…”

Nanomaterials: small particles show huge possibilities for cancer immunotherapy

“…However, the poor stability of STING agonists and limited cell permeability have limited its promotion in the clinical setting. With the emergence of tumor immunotherapy, researchers have discovered that metal ions play an important role in immunomodulation and have proposed the concept of "metal immunotherapy" [ 240 , 241 ]. Moon et al [ 242 ] found that Mn 2+ could significantly enhance the activity of STING agonist IFN-I through screening and designed a self-assembled nanoparticle CMP (CDN-Mn 2+ particle) based on Mn 2+ and CDN STING agonist, and prepared CMP CDA by modification.…”