# Photoactivatable immunomodulator polyprodrugs for boosting synergistic antitumor immunity of STING agonists and IDO inhibitors

## TL;DR

This paper introduces a new nanomedicine that combines light-activated cancer treatments to boost the immune system's ability to fight tumors.

## Contribution

A novel photoactivatable polyprodrug is developed to simultaneously deliver STING agonists and IDO inhibitors for spatiotemporal antitumor immunity.

## Key findings

- The polyprodrug micelles effectively target the endoplasmic reticulum and release drugs upon light exposure.
- In vivo experiments showed an 88% tumor suppression rate due to synergistic immune activation.
- The combination of PDT, STING activation, and IDO inhibition enhances antitumor immunity.

## Abstract

Rationale: Stimulator of interferon genes (STING) activation within tumors can inevitably enhance the activity of indoleamine 2,3-dioxygenase (IDO). However, IDO will convert tryptophan (Trp) into kynurenine (Kyn), which can inhibit Trp-sensitive T cells functional activity and induce immunosuppressive effects. The efficient nanomedicines for combination of STING agonist and IDO inhibitor have been rarely explored.

Methods: A diblock polymer polyprodrug was synthesized with the IDO inhibitor 1-methyl-tryptophan (1-MT) linked by thioketal bonds and the photosensitizer 5,10,15,20-tetraphenylporphyrin (TPP) in the hydrophobic block as well as endoplasmic reticulum (ER) targeting group (4-methylphenyl) sulfonamide in the hydrophilic block. After self-assembly in aqueous solution, the micelles loading STING agonist SR-717 (SR@ET-PMT) can be formed with a high loading efficiency. After cellular internalization, the micelles can target ER. Upon exposure to light irradiation of 650 nm, reactive oxygen species (ROS) can be generated to break thioketal bonds and dissociate the micelles to release 1-MT and STING agonist. Accompanied by photodynamic therapy (PDT), STING activation and IDO inhibition are achieved simultaneously.

Results:
In vitro observation reveals the PDT effect, ER targeting, and photoactivated drug release. In vivo animal model results demonstrate that the photoactivatable immunomodulator polyprodrug micelles show excellent tumor accumulation and potent immune activation capability to inhibit solid tumors. The PDT effect, STING activation, and IDO inhibition synergistically activate in vivo antitumor immunity. Finally, SR@ET-PMT can attain an 88% suppression rate of solid tumors due to the potent immunotherapeutic efficacy.

Conclusion: The photoactivatable immunomodulator polyprodrugs are successfully prepared to simultaneously deliver STING agonists and IDO inhibitors, which represent a promising nanomedicine for the spatiotemporal activation of synergistic antitumor immunity.