indoximod (NLG8189) / Lumos Pharma - LARVOL DELTA

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

Resource-efficient instruction tuning of large language models for biomedical named entity recognition. (PubMed, J Biomed Inform) - "NERLlama3.1 outperformed LLMs fine-tuned with full parameter updates, despite requiring significantly fewer computational resources. Moreover, it exhibited substantially superior in-domain generalization capabilities compared to traditional pre-trained language models. Its low resource demands, high performance, and strong generalization enhance its applicability and utility across diverse clinical BioNER tasks."

Journal • LAMA3

Indoximod Attenuates Inflammatory Responses in Acetic Acid-Induced Acute Colitis by Modulating Toll-like Receptor 4 (TLR4) Signaling and Proinflammatory Cytokines in Rats. (PubMed, Medicina (Kaunas)) - "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."

IO biomarker • Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Mucositis • Oncology • Ulcerative Colitis • PTX3 • TLR4 • TNFA

Multi-bioactive poly(amino acid)-metal-organic framework nanocomposite for reinforced cascading photodynamic immunotherapy of cancer. (PubMed, Biomaterials) - "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."

Journal • Breast Cancer • Oncology • Solid Tumor • CALR

Local delivery of IL-12 mRNA and indoximod prodrug potentiates antitumor immunity by increasing T cell effector function. (PubMed, J Control Release) - "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."

IO biomarker • Journal • Oncology • CD4 • CD8 • FOXP3 • IFNG • IL12A • TNFA

Trogocytosis-mediated acquisition of MHC class II molecules from plasmacytoid dendritic cells confers donor-specific immune tolerance to CD8+CD45RClow/- regulatory T cells. (PubMed, Mol Immunol) - "MHC-II+CD8+CD45RClow/-Tregs generated through trogocytosis exhibit donor-specific suppressive function. Moreover, in vitro generation of MHC-II+CD8+CD45RClow/-Tregs offers a potential alternative approach to induce donor-specific immune tolerance through adoptive transfer."

Journal • Transplantation • CD8 • IFNG • IL10 • IL2RA

Phospholipase A2 Group IIA activates Indoleamine 2,3-dioxygenase 1 to drive the progression of pulmonary fibrosis. (PubMed, Free Radic Biol Med) - "In this study, we characterized the critical role of PLA2G2A in pulmonary fibrosis (PF) in both human patients and bleomycin (BLM)-induced PF mouse models...For therapeutic strategy, we administered Varespladib (a PLA2G2A inhibitor) and Indoximod (the selective IDO1 inhibitor) to the animals, both of which were found to mediate the progression of PF. Our findings suggest that PLA2G2A plays a central role in pro-fibrotic processes by modulating epithelial cells and fibroblasts, thereby promoting extracellular matrix production. Given its involvement in PF pathogenesis, PLA2G2A may serve as a potential therapeutic target for PF, with PLA2G2A inhibitors offering a promising strategy for clinical treatment."

IO biomarker • Journal • Fibrosis • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • IDO1 • NLRP3 • PLA2G2A • STING

Albumin-based synergistic chemiexcited photodynamic biomimetic nanoreactor overcoming adaptive immune resistance for enhanced cancer immunotherapy. (PubMed, Int J Biol Macromol) - "CC@HSA/GOX@Z(Arg/1-MT)m could maintain its immune-promoting effects and alleviate post-treatment immune tolerance induced by elevated IDO expression. These findings demonstrated that the combination of IDO inhibitor and PDT represents a promising strategy for enhancing the immune response and ultimately inhibiting tumor growth."

IO biomarker • Journal • Oncology

IDO1 induced macrophage M1 polarization via ER stress-associated GRP78-XBP1 pathway to promote ulcerative colitis progression. (PubMed, Front Med (Lausanne)) - "Colitis was induced in mice via dextran sulfate sodium (DSS) treatment and subsequently treated with oral administration of 1-methyl-DL-tryptophan (1-MT), an inhibitor of IDO1 pathway...Additionally, the catalytic effect exerted by IDO1 overexpression on M1 polarization was neutralized by employing an inhibitor targeting the endoplasmic reticulum (ER) stress pathway. Thus, our findings suggest that IDO1 may promote UC progression by skewing macrophages towards M1 polarization through ER stress-associated GRP78-XBP1 pathway."

IO biomarker • Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • HSPA5 • IDO1 • XBP1

1-methyl-tryptophan improves anxiety-like behavior in colitis mice by inhibiting neuroinflammation, promoting cell regeneration and decreasing apoptosis. (PubMed, Clin Exp Immunol) - "Overall, these results suggest that 1-MT improved anxiety-like behaviors in mice with colitis by decreasing neuroinflammation, promoting neurogenesis and cell proliferation, and reducing apoptosis."

IO biomarker • Journal • Preclinical • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Mood Disorders • Psychiatry • BAX • BCL2 • DCX • IL1B • PCNA

Psilocin alleviates acute itch in mice: possible involvement of 5-HT2A receptors and kynurenine pathway. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Eight mice were randomly assigned to each of the study groups receiving either normal saline, compound 48/80, psilocin (0.3, 1, and 3 mg/kg), or psilocin (1 mg/kg) + 1-MT (0.3 mg/kg)...Our findings offer a novel repositioning for psilocin. This may be particularly beneficial for psychological conditions accompanied by pruritus."

Journal • Preclinical • Dermatology • Pruritus • Psychiatry • TLR4 • TNFA