IDO Inhibitor (Qilu Pharm)

Primary or acquired mutations in RAS/RAF genes resulting in cetuximab resistance have limited its clinical application in colorectal cancer (CRC) patients. The mechanism of this resistance remains unclear. RNA sequencing from cetuximab‐sensitive and ‐resistant specimens revealed an activation of the tryptophan pathway and elevation of IDO1 and IDO2 in cetuximab‐resistant CRC patients. In vitro, in vivo, and clinical specimens confirmed the upregulation of IDO1and IDO2 and the Kyn/Trp after cetuximab treatment. Additionally, the IDO inhibitor, epacadostat, could effectively inhibit the migration and proliferation of cetuximab‐resistant CRC cells while promoting apoptosis. Compared to epacadostat monotherapy, the combination of cetuximab and epacadostat showed a stronger synergistic anti‐tumor effect. Furthermore, in vivo experiments confirmed that combination therapy effectively suppressed tumor growth. Mechanistically, KEGG pathway analysis revealed the activation of the IFN‐γ pathway in cetuximab‐resistant CRC tissues. Luciferase reporter assays confirmed the transcriptional activity of IDO1 following cetuximab treatment. Silencing IFN‐γ then suppressed the upregulation induced by cetuximab. Moreover, we observed that the combination reduced the concentration of the tryptophan metabolite kynurenine, promoted the infiltration of CD8+ T lymphocytes, and enhanced the polarization of M1 macrophages within the tumor microenvironment, thereby exerting potent anti‐tumor immune effects. Overall, our results confirm the remarkable therapeutic efficacy of combining cetuximab with epacadostat in cetuximab‐resistant CRC. Our findings may provide a novel target for overcoming cetuximab resistance in CRC.

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.