indoximod (NLG8189) / Lumos Pharma - LARVOL DELTA

Estrogen regulates cognitive function in APP/PS1 female mice via modulation of IDO1-mediated Trp/Kyn metabolism through ERβ. (PubMed, Horm Behav) - "This study used APP/PS1 transgenic female mice with ovariectomy (OVX),E2, IDO1 inhibitor (1-MT), and agonists and antagonists of estrogen receptors to explore the potential roles of estrogen and IDO1 in AD...Furthermore, the ERβ antagonist could reverse the effects of E2 and the ERβ agonist had comparable effects to E2 on the Trp/Kyn pathway. These findings indicate that E2 has positive effects on the cognitive function of the APP/PS1 female mice undergoing OVX, and the mechanism may be related to the modulation of IDO1-mediated Trp/Kyn pathway via activation of ERβ."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Immunology • Inflammation • ER • IDO1

Biomimetic Iridium-Based Photothermal Nanozyme to Trigger Ferroptosis and Pyroptosis and Activate the cGAS-STING Pathway for Improved Tumor Immunotherapy. (PubMed, Adv Sci (Weinh)) - "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."

Journal • Oncology • CGAS • STING

Enhanced Upconversion Luminescent Nanocarrier for Effective Tumor-Targeted Photodynamic Therapy Combined with Immunotherapy. (PubMed, Adv Healthc Mater) - "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."

Journal • Oncology • CD4 • CD8 • FOXP3

Iridium(III) and rhenium(I) complexes containing an IDO inhibitor induce apoptosis and pyroptosis. (PubMed, J Inorg Biochem) - "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."

IO biomarker • Journal • Cervical Cancer • Oncology • Solid Tumor • GSDME

Chemo-immunotherapy Using Ibrutinib Plus Indoximod for Patients With Pediatric Brain Cancer (clinicaltrials.gov) - P1 | N=37 | Recruiting | Sponsor: Theodore S. Johnson | Trial completion date: Sep 2026 ➔ Sep 2028 | Trial primary completion date: Aug 2026 ➔ Mar 2028

Trial completion date • Trial primary completion date • Brain Cancer • Ependymoma • Glioblastoma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor

Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG (clinicaltrials.gov) - P2 | N=130 | Active, not recruiting | Sponsor: Theodore S. Johnson | Recruiting ➔ Active, not recruiting | Trial primary completion date: Oct 2025 ➔ Aug 2026

Enrollment closed • Trial primary completion date • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Ependymoma • Glioblastoma • Glioma • Medulloblastoma • Oncology • Pediatrics • Solid Tumor

Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8 + T cell-macrophage interactions. (PubMed, bioRxiv) - "These findings reveal specific mechanisms exploited by Mtb to maintain intra-granuloma persistence and underscore immune responses. Future vaccine and therapeutic design should consider these immunoregulatory features to achieve better control of Mtb infection."

IO biomarker • Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CD4 • CD8 • IDO1

Agathisflavone Modulates the Kynurenine Pathway and Glial Inflammatory Responses with Implications for Neuroprotection. (PubMed, Int J Mol Sci) - "This study evaluated whether agathisflavone (1 µM) modulates these responses in human and murine astrocytes and microglia exposed to inflammatory activation with lipopolysaccharide (LPS, 1 µg/mL), excitotoxic activation of NMDA receptors with quinolinic acid (QUIN, 500 µM), or inhibition of the KP rate-limiting enzyme indoleamine 2,3-dioxygenase 1 (IDO1) with 1-methyl tryptophan (1-MT, 1.5 μM)...Finally, astrocyte-conditioned medium from FAB-treated cells increased the viability of neuron-like PC12 cells by up to 40%. Collectively, these findings show that FAB confers cytoprotective and anti-inflammatory actions on glial cells, modulates KP signalling in a context-dependent manner, and supports neuronal survival under neuroinflammatory conditions."

IO biomarker • Journal • Inflammation • FAP • GFAP • IDO1 • IL1B

Modification-Driven Nanocarriers: Ovarian Cancer Cell Membrane- Camouflaged Indoximod/Doxorubicin Co-Delivery Systems for Synergistic Immunochemotherapy. (PubMed, Adv Healthc Mater) - "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."

IO biomarker • Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • CD8

Advanced in Co-Delivery, Controllable Therapy using Microneedle: From Design to Therapeutic Effects. (PubMed, Pharm Res) - "For example, a dual-drug MN co-loaded with an anti-PD-L1 antibody and 1-methyl-D,L-tryptophan (1-MT) achieved prolonged intratumoral retention and enhanced antitumor efficacy...The integration of nanocarriers and responsive polymers has expanded the therapeutic potential of MN-based systems, enabling precise, localized, and sustained co-delivery of active agents. Finally, current challenges including large-scale manufacturing, reproducibility, clinical validation, and regulatory approval are discussed to outline future directions for translating MN-based dual-drug delivery into clinical practice."

Journal • Review • Diabetes • Metabolic Disorders • Oncology

Indoleamine 2,3-dioxygenase 1 (IDO1) promotes immune effector cell-associated neurotoxicity syndrome (ICANS) after CAR-T therapy by disrupting brain endothelial cell integrity via KYNU–AA–Wnt/β-catenin pathway (ASH 2025) - "Mice were treated with the IDO1 inhibitor 1-methyltryptophan (1-MT), and the integrity of the blood-brain barrier (BBB) and expression of tightjunction proteins were subsequently analyzed... IDO1 promotes ICANS by impacting brain endothelial cell integrity through KYNU-AA-Wnt/β-catenin pathways. Targeting IDO1 may offer a therapeutic strategy to reduce neurotoxicity in CAR-Ttherapy."

IO biomarker • CNS Disorders • Cognitive Disorders • Hematological Malignancies • Lymphoma • Mood Disorders • Non-Hodgkin’s Lymphoma • Psychiatry • CLDN1 • IDO1 • KYNU • OCLN • TJP1

Bifidobacterium BX520 supplementation prevents neuroinflammation in necrotizing enterocolitis by inhibiting IDO1 through the gut-brain axis (ASH 2025) - "WB resultsshowed that BX520 significantly inhibited the IDO1 protein level in the hippocampus of NEC rats andmarkedly reduced the expression of inflammatory factors IL-1β and NF-κB. Intervention on NEC with theIDO1 inhibitor 1-MT demonstrated that targeted inhibition of IDO1 could significantly decrease the levelsof IL-1β and NF-κB proteins in the brain of NEC.ConclusionThe supplementation of Bifidobacterium BX520, which produces high-yield indole metabolites, canimprove the intestinal barrier by activating the intestinal AHR in NEC, and inhibit the expression of brainIDO1, thereby ameliorating the brain IL-1β and NF-κB inflammatory responses in NEC."

IO biomarker • Gastroenterology • Gastrointestinal Disorder • Inflammation • Metabolic Disorders • IDO1 • IL1B • OCLN • TJP1

MARCO antibody enhances anti-tumor immunity and immunotherapy efficacy (ESMO Asia 2025) - "Furthermore, MARCO blockade enhances the efficacy of IDO1 inhibitor indoximod. In in vitro , we induced myeloid-derived suppressor cells (MDSCs) differentiation using Krasˆ(LSL-G12D/+); p53ˆ(flox/flox) (KP) cells or LLC cells in mouse, and A549 or HCC827 cells in human... MARCO expression on MDSCs is correlates with IDO1 and may be regulated by the STAT3 pathway in TME. Tumor-derived exosomes contribute to this process. Anti-MARCO antibodies demonstrate anti-tumor effects both in vitro and in vivo, and exhibit synergistic activity with IDO1 inhibition."

Clinical • IO biomarker • Lung Cancer • Oncology • Solid Tumor • KRAS

Robust activation and clonal expansion of early, non-exhausted, stem-like endogenous T cells induced by chemo-immunotherapy treatment in patients with pediatric brain tumors is predictive of clinical outcome (SNO 2025) - P1, P2 | "We analyzed longitudinal blood samples from 52 patients with pediatric CNS tumors treated with indoximod plus either chemotherapy or chemotherapy plus BTK-inhibitor ibrutinib from trials NCT02502708, NCT04049669, NCT05106296. Treatment-expanded clones making up the CEI were an average of 100-fold more likely to be found in pre-treatment tumor biopsies by TCR-beta sequencing than random naïve T cells from the same patient; and up to 80% of CD8+ CEI T cells in circulation matched clonotypes found in tumor biopsies while on treatment. To our knowledge, this is the first report of immunotherapy-induced activation and clonal expansion of endogenous T cells in children."

Clinical • Clinical data • Brain Cancer • CNS Tumor • Oncology • Pediatrics • Solid Tumor • CD8

Robust activation and clonal expansion of early, non-exhausted, stem-like endogenous T cells induced by chemo-immunotherapy treatment in patients with pediatric brain tumors is predictive of clinical outcome (SNO 2025) - P1, P2 | "We analyzed longitudinal blood samples from 52 patients with pediatric CNS tumors treated with indoximod plus either chemotherapy or chemotherapy plus BTK-inhibitor ibrutinib from trials NCT02502708, NCT04049669, NCT05106296. Treatment-expanded clones making up the CEI were an average of 100-fold more likely to be found in pre-treatment tumor biopsies by TCR-beta sequencing than random naïve T cells from the same patient; and up to 80% of CD8+ CEI T cells in circulation matched clonotypes found in tumor biopsies while on treatment. To our knowledge, this is the first report of immunotherapy-induced activation and clonal expansion of endogenous T cells in children."

Clinical • Clinical data • Brain Cancer • CNS Tumor • Oncology • Pediatrics • Solid Tumor • CD8

Robust activation and clonal expansion of early, non-exhausted, stem-like endogenous T cells induced by chemo-immunotherapy treatment in patients with pediatric brain tumors is predictive of clinical outcome (WFNOS 2025) - P1, P2 | "We analyzed longitudinal blood samples from 52 patients with pediatric CNS tumors treated with indoximod plus either chemotherapy or chemotherapy plus BTK-inhibitor ibrutinib from trials NCT02502708, NCT04049669, NCT05106296. Treatment-expanded clones making up the CEI were an average of 100-fold more likely to be found in pre-treatment tumor biopsies by TCR-beta sequencing than random naïve T cells from the same patient; and up to 80% of CD8+ CEI T cells in circulation matched clonotypes found in tumor biopsies while on treatment. To our knowledge, this is the first report of immunotherapy-induced activation and clonal expansion of endogenous T cells in children."

Clinical • Clinical data • Brain Cancer • Pediatrics • Solid Tumor • CD8

Robust activation and clonal expansion of early, non-exhausted, stem-like endogenous T cells induced by chemo-immunotherapy treatment in patients with pediatric brain tumors is predictive of clinical outcome (WFNOS 2025) - P1, P2 | "We analyzed longitudinal blood samples from 52 patients with pediatric CNS tumors treated with indoximod plus either chemotherapy or chemotherapy plus BTK-inhibitor ibrutinib from trials NCT02502708, NCT04049669, NCT05106296. Treatment-expanded clones making up the CEI were an average of 100-fold more likely to be found in pre-treatment tumor biopsies by TCR-beta sequencing than random naïve T cells from the same patient; and up to 80% of CD8+ CEI T cells in circulation matched clonotypes found in tumor biopsies while on treatment. To our knowledge, this is the first report of immunotherapy-induced activation and clonal expansion of endogenous T cells in children."

Clinical • Clinical data • Brain Cancer • Pediatrics • Solid Tumor • CD8

Lactobacillus fermentum ATCC 9338 ameliorates immune dysregulation via indoleamine 2, 3-dioxygenase through modulating gut microbial diversity of chronic unpredictable mild stressed mouse. (PubMed, Metab Brain Dis) - "This study examined the role of Lactobacillus fermentum (LF) and 1-methyl-D-tryptophan (1-MT) on IDO regulation, proinflammatory cytokine responses, and gut microbial diversity in chronic unpredictable mild stress (CUMS) depression model...These results suggest that LF alleviates stress-induced neuroinflammatory and immune changes by modulating IDO activity in the tryptophan pathway. The findings highlight the therapeutic potential of LF as a microbiota-based intervention for regulating neuroinflammation and mood disorders such as depression."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Mental Retardation • Mood Disorders • Psychiatry

IDO Inhibition by 1-Methyltryptophan: Unlocking New Paths to Treat Ovarian Dysfunction and Hormonal Imbalance in PCOS. (PubMed, Iran J Pharm Res) - "To investigate the effects of IDO inhibition on ovarian morphology and insulin signaling in a PCOS rat model, evaluating its potential as a therapeutic approach compared to metformin. These findings support 1-MT as a promising therapeutic candidate for PCOS management and improving ovarian function. However, these results are from a short-term animal study, and further clinical trials are necessary to assess long-term efficacy and safety."

IO biomarker • Journal • Endocrine Disorders • Immunology • Inflammation • Polycystic Ovary Syndrome • IRS1 • PI3K

IDO-Mediated Immune and Metabolic Dysregulation in Schwann Cells Exposed to Mycobacterium leprae. (PubMed, Cells) - "Inhibition of IDO with 1-methyl-L-tryptophan (1-MT) reduced Schwann cell viability and metabolic activity in response to M. leprae...IDO induction contributes to immune regulation and cellular stress, while its inhibition disrupts cell viability and promotes antioxidant gene expression. These results position IDO as a potential therapeutic target for modulating host-pathogen interactions and mitigating nerve damage in leprosy."

IO biomarker • Journal • Immune Modulation • Immunology • Infectious Disease • Metabolic Disorders • Pain • GPX4 • HMOX1

IDO and TDO inhibitors in cancer immunotherapy: mechanisms, clinical development, and future directions. (PubMed, Front Pharmacol) - P1 | "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."

Journal • Review • Oncology • TDO2

DYSFUNCTIONAL KYNURENINE METABOLISM PROMOTES NEUROINFLAMMATION DURING HEPATIC ENCEPHALOPATHY DEVELOPMENT (AASLD 2025) - "Oral administration of 1-MT, an IDO inhibitor, suppressed IL1b and Icam1 in the BDL mice. The brain immune and metabolomic profiling of the mouse model and patients delineated Kynurenine as a novel immunometabolic factor increased early in HE development. Kynurenine could be a novel biomarker and therapeutic target of HE."

CNS Disorders • Fibrosis • Hepatic Encephalopathy • Hepatology • Immunology • Inflammation • Metabolic Disorders • Mood Disorders • Psychiatry • ICAM1 • IL1B

IDO Activation Affects BDNF/TrkB Signaling Pathway, Oxidative Stress, and Mitochondrial Enzymatic Activities in Temporal Lobe Epilepsy. (PubMed, Curr Issues Mol Biol) - "TLE was induced with 300 mg/kg pilocarpine. 1-MT intervention reversed all these pathological changes, restoring levels to near-control status. This indicates IDO activation promotes TLE progression, which is associated with modulation of the BDNF/TrkB signaling pathway, exacerbation of oxidative stress, and impairment of mitochondrial complex I/IV activities-supporting IDO as a potential therapeutic target for TLE."

IO biomarker • Journal • CNS Disorders • Epilepsy • CAT • IDO1

A novel AIE photosensitizer for combination photodynamic immunotherapy via autophagy activation and tumor microenvironment modulation. (PubMed, Eur J Med Chem) - "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."

Biomarker • IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • FOXP3

Inhibition of Indoleamine 2,3-dioxygenase by 1-Methyl-D-tryptophan (1-MT) rescued PTSD-like symptoms via downregulation of neuroinflammation and NMDA receptor. (PubMed, Eur J Pharmacol) - "By inhibiting IDO and reducing neuroinflammation, it further lessened the overexpression of N-Methyl-D-Aspartate (NMDA) receptor subunit NR1. Overall findings strongly suggest that 1-MT could serve as a potential therapeutic agent to treat PTSD by alleviating the TNF-α/NF-κB/IDO signaling pathway."

IO biomarker • Journal • CNS Disorders • Inflammation • Mood Disorders • Post-traumatic Stress Disorder • TNFA