navoximod (NLG919) / Lumos Pharma - LARVOL DELTA

Supramolecular immunomodulatory hydrogelator potentiates CAR-T therapy with long-lasting endogenous immunity toward solid tumor eradication. (PubMed, Sci Adv) - "This hydrogel forms an in situ scaffold that serves as a sustained-release reservoir, enabling continuous co-delivery of CAR-T cells along with immunomodulatory agents-NLG919 (an IDO-1 inhibitor) and DPPA-1 (a PD-L1 antagonistic peptide)-to synergistically remodel the immunosuppressive tumor microenvironment and promote robust tumor recognition and elimination...In murine models of aggressive melanoma, metastatic breast cancer, and postoperative glioma, a single local administration of the hydrogel resulted in significant suppression of tumor growth, rechallenge, metastasis and recurrence. By integrating localized CAR-T cell delivery with in situ immune reprogramming, this system represents a versatile and clinically translatable platform that substantially improves the efficacy of CAR-T cell therapy against solid tumors."

Journal • Brain Cancer • Breast Cancer • Glioma • Hematological Disorders • Hematological Malignancies • Melanoma • Oncology • Solid Tumor

Specific Adsorption of Tumor-Affinity Proteins to Improve Tumor Accumulation for Targeted Imaging and Therapy. (PubMed, Small) - "By co-loading immunomodulator NLG919 and AuPt nanocrystals (chemodynamic agent), the nanoplatforms demonstrate excellent specific adsorption capacity of tumor-affinity proteins including transferrin and fibronectin...Moreover, the intrinsic fluorine atoms serve as built-in probes for background-free 19F MRI, enabling non-invasive and real-time monitoring of nanoplatform biodistribution. This work provides a brand-new idea for the design of nanotheranostics with good anti-macrophage phagocytosis capacity and excellent tumor accumulation ability for imaging-guided therapy."

Journal • Oncology

Akkermansia muciniphila-derived postbiotics reprogram immune balance to combat sepsis via the IDO1/Kyn/AhR metabolic axis. (PubMed, J Adv Res) - "This study highlights the protective role of ALOS in sepsis and identifies the IDO1-Kyn-AhR immune axis as the major underlying mechanism."

IO biomarker • Journal • Infectious Disease • Septic Shock • IDO1

Sulfur Vacancy-Enriched Cu4SnS4-x Nanosheets Enable Synergistic Cuproptosis, Photothermoelectric Catalytic and Immunotherapy. (PubMed, Angew Chem Int Ed Engl) - "In this study, we introduce a defect engineering strategy to synthesize sulfur vacancies (Sv) enriched Cu4SnS4-x nanosheets with promising thermoelectric properties, followed by loading small-molecule inhibitor NLG919...This integrated approach achieves high efficiency (96%) and long-term anticancer efficacy. These findings may provide valuable insights for advancing thermoelectric materials in tumor therapy."

Journal • Oncology • CAT

A Platinum(IV) Metallo-Stapling Approach to Tumor-Specific Prodrugs for Targeted Chemo-Immunometabolic Cancer Therapy. (PubMed, Angew Chem Int Ed Engl) - "Upon reaching the tumor microenvironment, the construct undergoes dual-payload release to liberate platinum drug and the IDO-1 inhibitor NLG919, eliciting a robust immunogenic cell death cascade while simultaneously reversing immunosuppression. Furthermore, a combination with an aPD-L1 immune checkpoint blockade produces a marked synergistic antitumor response. This work establishes Pt(IV)-directed metallo-stapling as a versatile platform for precision cancer therapy, offering a generalizable strategy to chemically engineer a broad range of metalloprodrugs with enhanced tumor selectivity and biosafety."

Journal • Oncology • EGFR

Biomimetic TME-Responsive Nanotheranostics for Precise NIR-II Ratiometric Photoacoustic Imaging and Synergistic Immuno-Photothermal Therapy. (PubMed, Small) - "By encapsulating the IDO inhibitor NLG919 within a hollow mesoporous organosilica (HMON) shell and coating with cancer cell membrane (CCM), the system achieves superior tumor-targeting and synergistic immuno-photothermal effects...In bilateral tumor models, this integrated strategy effectively suppresses both primary lesions and distant metastases, demonstrating a potent systemic abscopal effect and durable antitumor immunity. Overall, this multifunctional nanoplatform provides a transformative strategy for NIR-II-guided precision medicine, offering a robust approach to eradicating metastatic and immunosuppressive malignancies."

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

A pH-sensitive polyprodrug nanoreactor to alleviate immunosuppression by programmed tumor-specific lactate depletion and indoleamine 2,3-dioxygenase 1 inhibition. (PubMed, J Control Release) - "Additionally, LOX-catalyzed lactate oxidation can generate abundant H2O2 to promote the release of NLG919 from the polyprodrug nanoreactors, thus reprogramming the immunosuppressive TME via cooperative lactate depletion and NLG919-mediated indoleamine 2,3-dioxygenase 1 inhibition in tumors. As a result, the intelligent polyprodrug nanoreactors can elicit intense antitumor immunity after intravenous administration, especially in combination with PD-L1 checkpoint blockade, thereby realizing effective and long-lasting suppression of primary and metastatic tumors without the concern of systemic toxicity."

Journal • Oncology • IDO1

IDO1 inhibition enables IFNγ-elicited responsiveness of pulmonary breast cancer metastases to hypoxia-directed tumoricidal agents (AACR 2024) - "In WT (wild type) mice with established 4T1 lung metastases, administration of the IDO1 inhibitors epacadostat, navoximod or indoximod each similarly resulted in rapid collapse of the metastatic tumor neovasculature and concomitantly increased intratumoral hypoxia and sensitivity to PERK inhibition...Combining chemotherapy with immune checkpoint blockade (ICB) is recognized as an effective strategy for treating lung cancer, with first-line therapy for some patients including the alkylating agent carboplatin in conjunction with pembrolizumab...Elevated intratumoral hypoxia has also previously been linked to increased expression levels of PDL1, a favorable indicator of ICB responsiveness, and we have confirmed the upregulation of PDL1 in 4T1 lung metastases following IDO1 inhibitor administration. Our data in the lung metastasis model support future studies to evaluate whether IDO1 inhibition can be effectively combined with evofosfamide and anti-PD1 treatment to improve..."

IO biomarker • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • IFNG • IL6 • PD-L1

Programmed Synergistic Photochemotherapy and Immune Activation of Triple Negative Breast Cancer Using Anti-PD-L1 Antibody-Conjugated Multifunctional Nanocapsules. (PubMed, Int J Nanomedicine) - "This project successfully constructed gold nanoshell-PLGA core NCs with PD-L1 antibody co-loaded with chemotherapeutic drugs doxorubicin and indoleamine 2,3-dioxygenase inhibitor NLG919. This diagnostic and therapeutic agent can be used for photochemotherapy, immunotherapy, and PAI to visualize and identify TNBC. The photochemotherapy mediated by the DNPA-aPD-L1 NCs we developed, combined with tumor microenvironment remodeling and immune activation, shows great promise for the diagnosis and treatment of TNBC."

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

Synergistic photodynamic therapy and IDO inhibition via a self-assembled nanomedicine potentiates PD-L1 blockade in gastrointestinal cancers. (PubMed, Biomater Adv) - "Here, we developed a self-assembled nanomedicine (VN NPs) co-loaded with verteporfin and the IDO-1 inhibitor NLG919, using TPGS as a stabilizer and long-circulating agent. In murine models of gastric and colon cancer, this combination strategy not only suppressed primary tumor growth but also significantly inhibited distant metastasis in colon cancer. This simple yet effective nanoplatform amplifies ICB efficacy and represents a promising translational approach for metastatic gastrointestinal malignancies."

Journal • Colon Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Carrier-free nanoreshapers disrupt cancer-associated fibroblast barriers and alleviate immunosuppression for synergistically potentiated immunotherapy. (PubMed, J Control Release) - "Herein, by using a one-pot approach, we developed a carrier-free nanoreshaper (QN NP) through coordinating manganese ions (Mn2+) with quercetin (Qc) and the indoleamine 2,3-dioxygenase 1 inhibitor NLG919 to lift these restrictions...Furthermore, combining QN NPs with an anti-PD-L1 antibody generated robust synergistic activity, leading to cooperative suppression of both primary tumor growth and pulmonary metastases. This carrier-free nanoreshaping strategy overcomes the dual challenges of stromal fibrosis and immune evasion, providing a promising paradigm for developing combined immunotherapies based on physical barrier disruption and microenvironment reprogramming."

Journal • Fibrosis • Immunology • Oncology • Solid Tumor • IDO1 • STING

A ROS/photo dual-responsive prodrug unimolecular micelle for boosted cancer immunotherapy. (PubMed, Asian J Pharm Sci) - "Herein, a reactive oxygen species (ROS)/photo dual-responsive amphipathic prodrug (denoted as PPTN) was designed and synthesized by linking NLG919, an indoleamine-2,3-dioxygenase (IDO) inhibitor, with the photosensitizer protoporphyrin IX (PpIX) by a thioketal moiety, and further modifying with mPEG2k...Moreover, PPTN induced simultaneous PDT-triggered immunogenic cell death (ICD) effect and specific IDO blockade to boost immune response, exhibiting potent suppression efficacy against primary and distant tumors. Overall, with the superiorities of easily controllable preparation procedures, synchronous drug delivery and ROS/photo dual-responsiveness, such a prodrug unimolecular micelle may represent a promising nanoplatform for photoactivated-immunotherapy."

Journal • Oncology

A dual-functional in situ hydrogel for delivering vitamin E-based lipid nanoparticles to enhance cancer immunotherapy. (PubMed, Mater Today Bio) - "Here, we synthesized a bioactive vitamin E-based ionizable lipid to formulate lipid nanoparticles co-loaded with IL-12 mRNA and the IDO1 inhibitor NLG919 (N@VEBLNP), which were subsequently embedded into polyether F127-diacrylate hydrogel (NVF Gel)...In 4T1 murine models, NVF Gel transformed the tumor environment into a more "immune-hot" state, effectively suppressed tumor growth and delayed postoperative recurrence. Collectively, NVF Gel provides a versatile platform for in situ cancer immunization and tumor microenvironment modulation."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IL12A

HIFU postoperative hypoxia-activated metal-organic frameworks modulate the tumor microenvironment to augment immunotherapy. (PubMed, J Nanobiotechnology) - "In addition, the immunosuppressive microenvironment exacerbated by postoperative hypoxia is degraded via the cooperation of NLG919, which blocks the IDO-1 signaling pathway and CaCO3, which consumes lactic acid. Based on these improvements, well-designed MOFs effectively inhibit bilateral tumor growth/metastasis and offer a successful paradigm for improving the overall prognosis of HIFU."

Biomarker • Journal • Oncology • IDO1

Engineered Bacterial Outer Membrane Vesicles Remodel Tumor Microenvironment for Enhanced Photodynamic Immunotherapy. (PubMed, Adv Healthc Mater) - "In this study, an engineered nanotherapeutic platform, PN@OMVs, is prepared by co-encapsulating the photosensitizer pheophorbide a (PPa) and the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919 within Escherichia coli BL21-derived outer membrane vesicles (OMVs)...Most importantly, a single administration combined with light irradiation could achieve tumor inhibition rates of 92.3% in primary tumors and 83.1% in distant tumors, without observable systemic toxicity. This study presents a promising paradigm of developing engineered OMVs to effectively remodel the TME for enhanced immunotherapy."

Biomarker • Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

Adverse pro-tumorigenic effects of IDO1 catalytic inhibitors mediated by the non-enzymatic function of IDO1 in tumor cells. (PubMed, Front Immunol) - "By studying the turnover of IDO1 protein in human tumor cells exposed to various IDO1 catalytic inhibitors, such as epacadostat, linrodostat, and navoximod, we show here that these molecules stabilize a non-enzymatic protein conformation of IDO1, independently of their mechanism of inhibition. In the thyroid carcinoma cell line FTC-133, the stabilized and non-enzymatic IDO1 protein promotes the proliferation and migration of the tumor, resulting in an adverse pro-tumorigenic effect. These results uncover an unexpected adverse effect of IDO1 inhibitors in the tumor microenvironment that overcomes the enzymatic inhibition of IDO1, and suggest protein degradation, rather than enzymatic inhibition, as a more effective approach to target IDO1 in the tumor microenvironment."

Journal • Oncology • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Carcinoma • IDO1

A Tailor-Made Biaryl-Stapled Peptide Nanoprodrug with Esterase-Triggered Dual Immunomodulation for Amplified Cancer Therapy. (PubMed, Nano Lett) - "This nanoprodrug platform features a biaryl-stapled proapoptotic peptide motif covalently conjugated to the indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919 via an ester bond, enabling esterase-triggered payload release within the tumors...In vivo studies demonstrate that this dual-immunomodulatory strategy significantly improves the efficacy of immunotherapy when combined with PD-L1 blockade. This work paves the way to advance the development of stapled peptide-based nanoplatforms as next-generation cancer immunotherapies."

Journal • Immunology • Oncology

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

Ligand-induced conformations and dynamic allosteric motions of IDO1 affecting the recruitment of a protein signaling partner. (PubMed, Commun Chem) - "A few IDO1 inhibitors have reached the clinical stage, including navoximod, epacadostat and linrodostat. Using second harmonic generation analysis (SHG) and molecular dynamics simulations, here we show that these clinical inhibitors can induce distinct allosteric motions in the enzyme that affect the stability of the transient signaling complex between IDO1 and Src tyrosine kinase. Next generation sequencing demonstrates that, despite sharing a similar ability to inhibit the enzyme's catalytic function, all three catalytic inhibitors modulate the IDO1's signaling function in different ways, regulating distinct transcriptomes in SKOV3 cells."

IO biomarker • Journal • Oncology • IDO1

Iridium(III)/rhenium(I) complexes bearing NLG919 as the ligand for enhanced triple-negative breast cancer therapy. (PubMed, Dalton Trans) - "The wound healing and colony assays also prove that these complexes significantly inhibit the metastasis of 4T1 cells. Furthermore, while inducing apoptosis, these complexes can also promote the release of damage-related molecular patterns (calreticulin (CRT), high mobility group protein b1 (HMGB1) and adenosine triphosphate (ATP)), thereby inducing immunogenic cell death (ICD)."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2 • CALR • CASP3 • HMGB1

Iodine-starch chromogenic nanoplatforms for photothermal precision and IDO-mediated colorectal cancer therapy. (PubMed, Int J Biol Macromol) - "They also encapsulated the IDO1 inhibitor NLG919 (IN@ASt NPs), enhancing immune modulation by downregulating IDO1 expression and reducing PTT-induced immunosuppression. This synergy induced immunogenic cell death, activated strong antitumor immunity, and inhibited lung metastasis in CRC models. Thus, this innovative platform leverages the biocompatibility of carbohydrate-based materials to address key challenges in CRC therapy."

IO biomarker • Journal • Colorectal Cancer • Immune Modulation • Immunology • Oncology • Solid Tumor

Expression of indoleamine-2,3-dioxygenase 1 in sebaceous glands and related tumors of the eyelid: a potential diagnostic target. (PubMed, Orbit) - "Prior to these findings, clinical management centered around surgical excision. The use of molecular compounds such as indoximob, epacadostat, BMS-986205 and navoximod, that directly target IDO1 opens new possibilities for targeting these tumors, improving clinical outcomes, and minimizing the morbidities often associated with surgery."

IO biomarker • Journal • Eye Cancer • Oncology • IDO1

Ultrasonic Cavitation-Manipulated Macrophages Hitchhiking Augments Delivery of Nanocarriers for Active and Efficient Cancer Therapy. (PubMed, Adv Healthc Mater) - "The OGNLN is perfluoropentane-loaded liposomal nanodroplet which consists of lipophilic prodrugs of elaidate-conjugated gemcitabine and NLG919...The nanodrugs penetrate tumor parenchyma and exhibit potent antitumor activity via chemo-immunotherapy. This study presents a promising strategy for efficient cancer therapy by utilizing ultrasound-regulated nanodrug-hitchhiking macrophages."

Journal • Oncology • Solid Tumor

Extracellular matrix-degradable polymer nanostimulants elicit potent immune responses in orthotopic pancreatic cancer via sono-activatable dual-drug synergism. (PubMed, Mater Today Bio) - "The SPNs were constructed by loading two immune drugs: toll-like receptor 7/8 agonist (R848) and indoleamine 2,3-dioxygenase inhibitor (NLG919), onto singlet oxygen (1O2)-responsive SPNs, and modifying their surface with hyaluronidase (HAase)...Consequently, the growth of orthotopic pancreatic tumors in mouse models is nearly inhibited, and tumor metastases are effectively suppressed. This study presents an ECM-degradable semiconducting polymer nanostimulant for multifaceted remodeling of the tumor microenvironment, enabling effective and precise immunotherapy of deep-seated orthotopic tumors."

Journal • Oncology • Pancreatic Cancer • Solid Tumor

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