navoximod (NLG919) / Lumos Pharma - LARVOL DELTA

Engineered Macrophages for Ultrasound-Triggered Drug Release and Enhanced Cancer Therapy (CIMT 2025) - "Esterified prodrugs of gemcitabine and NLG919 were encapsulated into lipid droplets containing perfluoropentane to construct liposome (OGNLN)...In vivo study demonstrated that OGNLN@MACs suppressed tumor growth and prolonged the survival of tumor-bearing mice.In summary, this study developed drug-loaded macrophages (OGNLN@MACs) that enables ultrasound-controlled drug release. This strategy enhances drug delivery efficiency and inhibits tumor progression in a mouse model."

Oncology

Reversing the immunosuppressive tumor microenvironment via "Kynurenine starvation therapy" for postsurgical triple-negative breast cancer treatment. (PubMed, J Control Release) - "Moreover, a single implantation of NLG919 + KYNase@Gel not only effectively inhibits the postoperative recurrence and metastasis in 4 T1 tumor-bearing mice, but also restrains the growth in an orthotopic TNBC mouse model. These findings highlight an innovative strategy to reinforce the antitumor immune response for the treatment of postsurgical TNBC."

Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • KYNU

Targeting matrix metalloproteinases activating and Indoleamine 2,3-dioxygenase suppression for triple-negative breast Cancer multimodal therapy. (PubMed, Int J Biol Macromol) - "Through self-assembly technology, this micelle effectively incorporates chemotherapy drugs (camptothecin (CPT) and cinnamaldehyde (CA)), reactive oxygen species (ROS) stimulants, nitric oxide (NO) donor and IDO inhibitor (NLG919), where CPT and CA have been reported to help generating ROS mainly in the mitochondrion...Experimental results demonstrate that the micelles exhibit significant anti-tumor effects both in vitro and in vivo, accompanied by favorable biocompatibility. This study provides new insights into the application of subcellular targeting drug delivery systems in TNBC treatment, potentially heralding a new breakthrough in TNBC therapy."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Drug repurposing through Biophysical Insights: Focus on Indoleamine 2,3-Dioxygenase and Tryptophan 2,3-Dioxygenase Dual Inhibitors. (PubMed, Cell Biochem Biophys) - "Despite attempts to use navoximod as a dual-specific inhibitor, its poor bioavailability and lack of clinical efficacy have hampered its utility...Alongside, the interaction profile with critical residues, strongly reinforced DB06292 (Dapagliflozin) as a compelling hit candidate. Finally, the reliability of the result was corroborated through a rigorous 200 ns molecular dynamics simulation, ensuring the stable binding of the hit against the target proteins. Considering the promising outcomes, we speculate that the proposed hit compound holds strong potential for the management of TNBC."

Journal • Oncology • Triple Negative Breast Cancer • IDO1 • TDO2

A novel NIR-dependent IDO-inhibiting ethosomes treatment melanoma through PTT/PDT/immunotherapy synergy. (PubMed, Colloids Surf B Biointerfaces) - "In this study, we prepared and characterized INEs, a novel ethosome composed of the photosensitizer IR251 and the Indoleamine-2, 3-dioxygenase (IDO) inhibitor NLG919...In conclusion, INEs represent a promising strategy for melanoma treatment by a combination of phototherapy and immunotherapy with high safety. This study provides new insights and a theoretical basis for the clinical treatment of melanoma."

Journal • Melanoma • Oncology • Solid Tumor • CD4 • CD8

Novel therapeutic targets uncovered by genome-wide integrative analysis in bronchopulmonary dysplasia. (PubMed, J Matern Fetal Neonatal Med) - "The Drug-Gene Interaction Database (DGIdb) predicted three drugs-LM10, navoximod, and ziprasidone-that potentially interact with these key genes. This integrative genome-wide analysis provides valuable insights into the genetic mechanisms underlying BPD. The findings facilitate the identification of novel therapeutic targets and pave the way for personalized treatment strategies for affected neonates."

Journal • Bronchopulmonary Dysplasia • Pulmonary Disease • Respiratory Diseases

Tumor Microenvironment-Responsive Nano-Immunomodulators for Enhancing Chimeric Antigen Receptor-T Cell Therapy in Lung Cancer. (PubMed, ACS Nano) - "The acidic TME induces the disassembly of FMANAC, followed by the drug release, in which C-C chemokine ligand 5 (CCL5) improves the disrupted chemotactic gradient within tumors, increasing CAR-T cell recruitment and infiltration into deep tissue; and NLG919 reverses indoleamine 2,3-dioxygenase (IDO)-mediated immunosuppression in TME to create a favorable environment for CAR-T cells to exert their killing function. In the H460 lung cancer animal model, this nanoregulatory strategy combined with engineered CD276 CAR-T cells, guided by multiplexed near-infrared-II fluorescence imaging for programmed administration, achieved significantly enhanced tumor treatment efficacy."

Biomarker • Journal • Hematological Disorders • Hematological Malignancies • Lung Cancer • Oncology • Solid Tumor • CD276

NIR-II photothermal therapy combined with activatable immunotherapy against the recurrence and metastasis of orthotopic triple-negative breast cancer. (PubMed, Nanoscale) - "At the same time, NLG NPs can be decomposed into the NLG919 monomer in the tumor microenvironment, which can effectively strengthen the immunogenic cell death-induced immune response. NIR-II PTT in synergy with IDO-1 blockade can effectively inhibit tumor growth and prevent tumor recurrence and metastasis. This work thus provides a safe, efficient and feasible method for the treatment of malignant tumors."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IDO1

Polyphenol-based pH-responsive nanoparticles enhance chemo-immunotherapy in pancreatic cancer. (PubMed, J Control Release) - "Herein, we propose a concise strategy to construct a biocompatible, polyphenol-based, pH-responsive nanoparticle to co-deliver docetaxel (DTX) and NLG919 (an IDO1 inhibitor) to significantly enhance chemo-immunotherapy for PDAC by remodeling the TME. FPND triggered an effective anti-tumor immune response, characterized by increased CD8+ T cells infiltration and decreased Treg recruitment, leading to significant inhibition of subcutaneous tumor growth in KPC mice through a combination of chemotherapy and immunotherapy. Overall, FPND nanoparticles showed excellent anti-tumor efficacy as a PDAC therapeutic strategy with broad potential in precision medicine."

Journal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8

An albumin-prodrug injectable formulation for synergistic cancer immunotherapy. (PubMed, J Colloid Interface Sci) - "Meanwhile, NLG919 regulates the recognition and killing of tumor cells by immune cells, effectively blocking the immunosuppression caused by IDO overexpression. This study highlights the potential of a tumor environment-responsive prodrug strategy to enhance the efficacy of immunotherapy, demonstrating the promising clinical translation of the novel MSA-NLG@BSA (PIF) formulation."

IO biomarker • Journal • Oncology • STING

Redox-responsive metal-organic framework nanocapsules enhance tumor chemo-immunotherapy by modulating tumor metabolic reprogramming. (PubMed, Mater Today Bio) - "DNMCs consist of an acidic and redox-sensitive metal-organic framework (MOF) encapsulating Doxorubicin (DOX) and the indoleamine-2,3-dioxygenase1 (IDO1) inhibitor NLG919. Overall, DNMCs exhibit significant tumor growth inhibition in pancreatic cancer patient-derived organoids (PDOs) and mouse models. This study presents a promising approach to enhancing chemo-immunotherapy by targeting tumor metabolic reprogramming and augmenting immune response against malignant tumors."

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Identification of putative Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) dual inhibitors for triple-negative breast cancer therapy. (PubMed, J Biomol Struct Dyn) - "Navoximod, a reliable dual-specific inhibitor, resulted in poor bioavailability and modest efficacy in clinical trials restricts its utility...In light of these findings, it is presumed that the proposed compound exhibits significant inhibitory activity. As a result, we speculate that further optimisation of NPACT00380 could be beneficial for the treatment and management of TNBC."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IDO1 • TDO2

Injectable supramolecular hydrogel co-loading abemaciclib/NLG919 for neoadjuvant immunotherapy of triple-negative breast cancer. (PubMed, Nat Commun) - "The neoadjuvant immunotherapy reduces tumor recurrence and pulmonary metastasis and prolongs the survival of animals. This hydrogel provides a potential platform for neoadjuvant immunotherapy of triple-negative breast cancer with reduced toxicity compared with free abemaciclib."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IDO1 • IL2

Pyruvate Kinase M2-Responsive Release of Paclitaxel and Indoleamine 2,3-Dioxygenase Inhibitor for Immuno-Chemotherapy of Nonsmall Cell Lung Cancer. (PubMed, Adv Sci (Weinh)) - "To address this issue, a smart peptide hydrogelator Nap-Phe-Phe-Phe-Lys-Ser-Thr-Gly-Gly-Lys-Ala-Pro-Arg-OH (Nap-T), which co-assembles with PTX and an IDO inhibitor GDC0919 to form a hydrogel GP@Gel Nap-T, is rationally designed. We find that GP@Gel Nap-T enhances the infiltration of tumor-infiltrating immune cells and reduces the number of immunosuppressive cells in either tumor tissues or tumor-draining lymph nodes, thus enhancing the immuno-chemotherapy of PTX toward NSCLC. With this PKM2-responsive drug release strategy, the smart peptide hydrogel platform might be applied for NSCLC treatment in clinic in near future."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • PKM

Stimulus Responsive Nanocarrier for Enhanced Antitumor Responses Against Hepatocellular Carcinoma. (PubMed, Int J Nanomedicine) - "We have developed a pH and reactive oxygen species (ROS) dual stimulus-responsive drug delivery system (PN@GPB-PEG NPs) loaded with chemotherapeutic paclitaxel (PTX) and indoleamine 2.3-dioxygenase (IDO) inhibitor NLG919, for HCC chemoimmunotherapy. In a mouse model of HCC, our nanoparticles effectively inhibited the growth of primary and recurrent tumors. These encouraging results highlight the potential of our nanocarrier system as an innovative therapeutic approach to address HCC primary tumor and postsurgical recurrence, providing hope for enhanced patient outcomes."

Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Biomimic Nanodrugs Overcome Tumor Immunosuppressive Microenvironment to Enhance Cuproptosis/Chemodynamic-Induced Cancer Immunotherapy. (PubMed, Adv Sci (Weinh)) - "Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and disrupt intracellular Cu homeostasis...Herein, a biomimic nanodrug (ECNM) is fabricated, of which ES, Cu2+ and NLG919 (an IDO1 inhibitor) are integrated via a self-assembly process and subsequently coated with 4T1 cell membrane...Furthermore, ECNM not only accelerates tumor regression but also gains a strong abscopal effect and displays the potential of tumor vaccination. Overall, ECNM can activate antitumor immunity via cuproptosis and CDT, together with TIM reversing, for cancer treatment."

Journal • Oncology

Tryptophan Metabolism in Obesity: The Indoleamine 2,3-Dioxygenase-1 Activity and Therapeutic Options. (PubMed, Adv Exp Med Biol) - "IDO-producing tumors show a high total IDO immunostaining score, and thus, using IDO inhibitors, such as Epacadostat, Navoximod, and L isomer of 1-methyl-tryptophan, seems an important modality for cancer treatment...Antitumor effects of imatinib are enhanced by increasing T-cell effector function in the presence of IDO inhibition. Combining IDO targeting with chemotherapy, radiotherapy and/or immunotherapy, may be an effective tool against a wide range of malignancies. However, there are some controversial results regarding the efficacy of IDO1 inhibitors in cancer treatment."

IO biomarker • Journal • Review • Alzheimer's Disease • Atherosclerosis • Bipolar Disorder • Cardiovascular • CNS Disorders • Cognitive Disorders • Coronary Artery Disease • Depression • Dyslipidemia • Genetic Disorders • Metabolic Disorders • Obesity • Oncology • Psychiatry • CTLA4 • IDO1 • IFNG

Transformable self-delivered supramolecular nanomaterials combined with anti-PD-1 antibodies alleviate tumor immunosuppression to treat breast cancer with bone metastasis. (PubMed, J Nanobiotechnology) - "In addition, the IDO-1 inhibitor NLG919 was loaded with Ce6-CD and Fc-pep-PEG to construct the supramolecular nanoparticle NLG919@Ce6-CD/Fc-pep-PEG (NLG919@CF)...Moreover, combined administration with an anti-PD-1 antibody further relieved immune suppression in the tumor microenvironment. This article presents a new strategy for the clinical treatment of breast cancer with bone metastasis and osteolysis."

Journal • Breast Cancer • Oncology • Solid Tumor

GSH-responsive polymeric micelles-based augmented photoimmunotherapy synergized with PD-1 blockade for eliciting robust antitumor immunity against colon tumor. (PubMed, J Nanobiotechnology) - "To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO2, IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA)...RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • TLR4

Amino Acid Metabolism-Regulated Nanomedicine for Enhanced Tumor Immunotherapy through Synergistic Regulation of Immune Microenvironment. (PubMed, Biomater Res) - "Herein, metabolism-regulated nanoparticles are prepared through metal coordination-driven assembly of an IDO1 inhibitor (NLG919) and a stimulator of interferon genes (STING) agonist (MSA-2) for enhanced immunotherapy...The antitumor immunity induced by nanoparticles significantly inhibited the development of primary and metastatic tumors, as well as B16 melanoma. Overall, this study provided a novel paradigm for enhancing tumor immunotherapy through synergistic amino acid metabolism and STING pathway activation."

Journal • Melanoma • Oncology • Solid Tumor • STING

Hypoxia-Specific Metal-Organic Frameworks Augment Cancer Immunotherapy of High-Intensity Focused Ultrasound. (PubMed, ACS Nano) - "Herein, a hypoxia-specific metal-organic framework (MOF) nanosystem, coordinated by Fe3+, hypoxic-activated prodrug AQ4N, and IDO-1 signaling pathway inhibitor NLG919, is developed for the potentiating immunotherapy of HIFU surgery...In vivo studies demonstrate that the MOF-mediated immunotherapy greatly inhibits the growth of primary/distant tumors and eliminates lung metastasis. This work establishes a robust delivery platform to improve immunotherapy and the overall prognosis of HIFU surgery with high specificity and potency."

Journal • Oncology • IDO1

Reprogrammed IDO-Induced Immunosuppressive Microenvironment Synergizes with Immunogenic Magnetothermodynamics for Improved Cancer Therapy. (PubMed, ACS Appl Mater Interfaces) - "In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

A theoretical study on the activity and selectivity of IDO/TDO inhibitors. (PubMed, Phys Chem Chem Phys) - "Furthermore, the binding and dissociation processes of the C1 inhibitor (NLG919) were simulated by the adaptive steering molecular dynamics (ASMD) method, which not only addressed the possible stable, metastable, and transition states for C1 inhibitor-IDO/TDO interactions, but also accurately predicted kinetic data for C1 inhibitor binding and dissociation. In conclusion, we have constructed a complete process from enzyme (IDO/TDO) conformational activation to inhibitor binding/dissociation and used the thermodynamic and kinetic data of each link as clues to verify the control mechanism of IDO/TDO on inhibitor selectivity. This is of great significance for us to understand the design principles of tumor immunotherapy drugs and to avoid drug resistance of immunotherapy drugs."

Journal • Oncology • IDO1

Intelligent nanovesicle for remodeling tumor microenvironment and circulating tumor chemoimmunotherapy amplification. (PubMed, J Nanobiotechnology) - "At present, despite 5-fluorouracil (5-FU), as a clinical first-line FOLFIRINOX chemo-drug, has achieved significant therapeutic effects...Therefore, a metal matrix protease-2 (MMP-2) and endogenous GSH dual-responsive liposomal-based nanovesicle, co-loading with 5-FU (anti-cancer drug) and NLG919 (IDO1 inhibitor), was constructed (named as ENP919@5-FU)...Moreover, the combination of ENP919@5-FU and PD-L1 antibody (αPD-L1) showed a synergistic anti-tumor effect on the PDAC model with abdominal cavity metastasis. Collectively, ENP919@5-FU nanovesicle, as a PDAC treatment strategy, showed excellent antitumor efficacy by remodeling tumor microenvironment to circulate tumor chemoimmunotherapy amplification, which has promising potential in a precision medicine approach."

Biomarker • IO biomarker • Journal • Tumor microenvironment • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • IFNG • MMP2

Ultra-small Janus Nanoparticle-induced Activation of Ferroptosis for Synergistic Tumor Immunotherapy. (PubMed, Acta Biomater) - "The production of ROS, consumption of GSH, and photothermal properties of MGNH make it possible for CDT/PTT activated ferroptosis, and synergistically disrupt and reprogram tumor growth and immunosuppressive tumor microenvironment with NLG919 and Mn2+-mediated activation of cGAS-STING pathway, achieving CDT/PTT/immunotherapy activated by ferroptosis. Meanwhile, ultra-small structural properties of MGNH facilitate subsequent metabolic clearance by the body, allowing for the minimization of potential biotoxicity associated with its prolonged retention."

IO biomarker • Journal • Oncology • GPX4