indoximod (NLG8189)

Here, an iridium (Ir)-based nanozyme (IIN) was constructed through coordination-driven co-assembly using photosensitizer indocyanine green (ICG), Ir, and indoleamine 2,3-dioxygenase (IDO) inhibitor NLG8189...Furthermore, it could suppress distant tumor progression by triggering the immune response, especially under photothermal irradiation, which was accompanied by increased DC maturation, M1 macrophage polarization, and T cell infiltration in tumor tissue. This study proposed a promising strategy for effective Ir-based nanozyme in tumor immunotherapy.

In this study, we produced near-infrared (NIR)-induced multi-shell upconversion nanoparticle (MUN)-based therapeutic nanocarriers co-loaded with chlorin e6 (Ce6) and indoximod (IND) (FMUN3-Ce6/IND) to combine tumor-targeted photodynamic therapy (PDT) with immunotherapy...Furthermore, the synergistic antitumor efficacy of FMUN3-Ce6/IND combining PDT and immunotherapy under in vivo conditions is demonstrated. These results suggest that multi-shell FMUN-based nanocarriers offer a promising platform for synergistic combination therapy, addressing the limitations of monotherapy with IDO inhibitors and overcoming the restricted tissue penetration and low ROS generation associated with conventional PDT.

Four novel Ir(III)/Re(I)-1-methyl-D-tryptophan conjugates (Ir-MT-1-2 and Re-MT-1-2) were designed and synthesized for the first time, among which 1-methyl-D-tryptophan (1-MT) is an indoleamine 2,3-dioxygenase (IDO) inhibitor...Mechanistic investigations revealed that these complexes selectively localized to mitochondria, inducing mitochondrial membrane potential (MMP) depolarization, elevating intracellular reactive oxygen species (ROS) levels, activating mitochondrial apoptotic pathways, and simultaneously inducing the cleavage of pyroptosis marker (GSDME) to cause pyroptosis. These results demonstrate the potential of combing transition metals with IDO inhibitors for cancer treatment.

In this study, a formulation of DOX/IND-loaded liposomes camouflaged with ovarian cancer cell membranes is successfully developed, and their stable physicochemical properties are confirmed. As an effective nanodrug delivery system, DOX/IND@cmLPs exhibited enhanced tumor-targeting and immune-mediated anticancer activity both in vitro and in vivo, indicating their potential as a platform for future combined chemotherapy and immunotherapy.

Among these, medications like Indoximod, Epacadostat, and Navoximod have shown promise in influencing the immune system and slowing tumor progression, while dual inhibitors like HTI-1090 try to address broader metabolic connections. The use of IDO/TDO inhibitors with conventional anticancer medications demonstrates their potential to reshape cancer treatment paradigms, contingent on further research to optimize efficacy and safety. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT03844438.

To address these challenges, we developed a novel photosensitizer (PS), TTVBO-1MT, by conjugating the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor 1-methyl-d-tryptophan (1-MT) to the aggregation-induced emission (AIE) PS TTVBO via a glutathione (GSH)-responsive linker...This combined effect promoted T-cell infiltration and triggered a systemic antitumor immune response. Overall, the results suggest that TTVBO-1MT enables autophagy-assisted immuno-photodynamic modulation of the tumor microenvironment (TME), offering significant therapeutic potential.

However, PAF levels remained elevated despite treatment, indicating limited efficacy in PAF-associated pathways. Indoximod exhibited anti-inflammatory effects in this acute colitis model, likely by downregulating key proinflammatory mediators.

In this study, a multi-bioactive nanocomposite consisting of hyaluronic acid-block-poly(1-methyl-d-tryptophan-co-l-glutamic acid) (HA-PMTG) and tetracarboxyl porphyrin-trivalent Fe(III) metal-organic framework (MOFTCPP-Fe) was developed for enhanced cascading PDIT...Furthermore, treatment with HA-PMTG@MOFTCPP-Fe on the primary tumor inhibited distant tumor growth through a bystander effect and prevented tumor recurrence by activating immune memory. Thus, the multi-bioactive HA-PMTG@MOFTCPP-Fe offers an effective cascading strategy to enhance the PDIT of cancer.

Also, by the elevated secretion of IL-12 cytokine, T cells release high levels of IFNγ, which is a central role in IL-12-mediated immunotherapy. This co-delivery system presents a promising strategy to overcome the limitations of single IL-12-mediated therapy by simultaneously promoting antitumor immune responses and inhibiting immunosuppressive mechanisms, thereby enhancing the overall efficacy of cancer immunotherapy.

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...Finally, SR@ET-PMT can attain an 88% suppression rate of solid tumors due to the potent immunotherapeutic efficacy. 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.

Tumor microenvironment (TME) immune profiling revealed that CDs-IND reduced IDO expression and recruited NK, NKT, and T cells. This study underscores the potential of combining the inherent pharmacological properties of CDs with indoximod-mediated immunotherapy, offering a promising strategy for precision breast cancer treatment.

Combining indoximod and oHSV significantly inhibited tumor growth, and induced antigen specific CD8+ T cell activation. These results suggest that inhibition of the IDO pathway could significantly block feedback immunosuppression during oncolytic virotherapy of glioblastoma.