# Targeting immune checkpoint therapy: The role of manganese in tumor immunotherapy

## TL;DR

This paper reviews how manganese enhances cancer immunotherapy by activating immune pathways and improving treatment effectiveness.

## Contribution

The paper provides a comprehensive review of manganese's role in modulating the cGAS-STING pathway and enhancing immune checkpoint therapy.

## Key findings

- Manganese modulates the cGAS-STING pathway to enhance immune checkpoint therapy.
- Manganese salts act as immune adjuvants, boosting both humoral and cellular immune responses.
- Manganese promotes immunogenic cell death, augmenting anti-tumor effects.

## Abstract

Cancer immunotherapy has emerged as a promising complement to traditional treatments such as radiotherapy and chemotherapy. Although conventional therapies remain central to cancer management, the potential of immunotherapy is increasingly recognized. Immune checkpoint therapy, a key strategy in tumor immunotherapy, has demonstrated significant efficacy against solid tumors. However, its clinical application is hindered by its limited response rate, necessitating efforts to optimize its effectiveness. Recent studies have highlighted the pivotal role of the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon gene (STING) pathway in immune checkpoint therapy. Manganese (Mn), an essential trace element, regulates the activity of CD8+ T and NK cells by modulating the cGAS-STING pathway. Furthermore, the combination of Mn with anti-programmed cell death protein 1 therapy has demonstrated promising anti-tumor effects. Mn also influences immunogenic cell death (ICD), further augmenting its potential as an adjunct to tumor immunotherapy. Despite a growing body of research on the role of Mn in modulating the cGAS-STING pathway and inducing ICD, comprehensive reviews that synthesize these findings and explore the potential of Mn in enhancing immune checkpoint therapy are still lacking. This review aimed to fill this gap by examining the immune mechanisms by which Mn enhances immune checkpoint therapy and its overall impact on tumor immunotherapy.

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•Mn2+ modulates the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon gene (STING) pathway and promotes immunogenic cell death to enhance immune checkpoint therapy efficacy.•Mn2+ binds to and activates cGAS, increasing its sensitivity to double-stranded DNA and promoting cyclic GMP-AMP (cGAMP) production.•Manganese salts (e.g., MnJ) act as potent immune adjuvants that enhance both humoral and cellular immune responses.

Mn2+ modulates the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon gene (STING) pathway and promotes immunogenic cell death to enhance immune checkpoint therapy efficacy.

Mn2+ binds to and activates cGAS, increasing its sensitivity to double-stranded DNA and promoting cyclic GMP-AMP (cGAMP) production.

Manganese salts (e.g., MnJ) act as potent immune adjuvants that enhance both humoral and cellular immune responses.