# ATP-fueled STING activation of manganese coordinated nanoagonist to boost antitumor immunity

## TL;DR

Researchers developed an ATP-powered nanoparticle that boosts immune response against tumors by activating the STING pathway and reprogramming immune cells.

## Contribution

A novel ATP-Mn coordination nanoparticle is introduced to enhance STING activation and antitumor immunity.

## Key findings

- ATP-Mn CNP activates cGAS-STING signaling and shifts macrophages to an antitumor phenotype.
- ATP-Mn CNP combined with checkpoint inhibitors eradicated tumors in 37.5% of mice and prolonged survival.
- The nanoparticle effectively enhances cytotoxic lymphocyte infiltration into tumors.

## Abstract

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway represents a central driver of innate immune activation, and manganese ion (Mn2+) has recently been identified as a potent modulator of this signaling axis. However, the application of Mn2+ is limited by its rapid clearance, nonspecific distribution and potential neurotoxicity. Inspired by the unique chemical structure and biological functions of adenosine triphosphate (ATP), we herein propose an ATP-Mn coordination nanoparticle (ATP-Mn CNP) to fuel cGAS-STING activation and antitumor immunity. We demonstrated that the phosphate groups of ATP could coordinate with Mn2+ and form stable, well-defined nanoparticles after lipid coating. ATP-Mn CNP significantly increased the expression of cGAS-STING-associated genes and activated the corresponding signaling cascades, and thus effectively polarized macrophages from tumor-supportive M2 to antitumor M1 phenotype. In vivo antitumor studies indicated that ATP-Mn CNP treatment significantly suppressed tumor growth, and reprogramed macrophages in tumors and draining lymph nodes, which thus facilitated the tumor infiltration of cytotoxic lymphocytes. Combination of ATP-Mn CNP with immune checkpoint inhibitors achieved 37.5% tumor eradication in MC38 murine models, and significantly prolonged mice survival. This study establishes an ATP-fueled coordination strategy that harnesses ATP as both an assembly ligand and an immune stimulator to enhance Mn-mediated STING activation.

Image 1

•ATP-Mn coordination nanoparticle (ATP-Mn CNP) synergistically potentiates cGAS-STING activation for cancer immunotherapy.•ATP not only drives the nanoparticle formation but synergizes with Mn2+ to amplify STING signaling.•ATP-Mn CNP reprograms macrophages and enhances cytotoxic lymphocyte infiltration in tumors.•Combining ATP-Mn CNP with checkpoint blockade achieves durable tumor suppression.

ATP-Mn coordination nanoparticle (ATP-Mn CNP) synergistically potentiates cGAS-STING activation for cancer immunotherapy.

ATP not only drives the nanoparticle formation but synergizes with Mn2+ to amplify STING signaling.

ATP-Mn CNP reprograms macrophages and enhances cytotoxic lymphocyte infiltration in tumors.

Combining ATP-Mn CNP with checkpoint blockade achieves durable tumor suppression.