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

<b>Rationale:</b> 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. <b>Methods:</b> 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. <b>Results:</b> <i>In vitro</i> observation reveals the PDT effect, ER targeting, and photoactivated drug release. <i>In vivo</i> 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 <i>in vivo</i> antitumor immunity. Finally, SR@ET-PMT can attain an 88% suppression rate of solid tumors due to the potent immunotherapeutic efficacy. <b>Conclusion:</b> 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.