evofosfamide (IMGS-101) / ImmunoGenesis - LARVOL DELTA

A biomimetic nanozyme platform for spatiotemporally programmed cascade catalysis and potentiated chemodynamic immunotherapy. (PubMed, J Colloid Interface Sci) - "Here, we report a biomimetic nanoplatform, CuO@MSN/TH302@GOx@CM (CMTGM), which integrates a programmed multi-enzyme cascade consisting of a copper oxide (CuO) core, a dendritic mesoporous silica (MSN) intermediate shell, the hypoxia-activated prodrug TH302, and surface-conjugated glucose oxidase (GOx)...In both in vitro and in vivo studies, CMTGM demonstrated efficient tumor targeting, robust tumor suppression, and favorable biosafety of in a 4 T1 breast cancer model. This study provides a generalizable strategy for the rational design of programmable catalytic nanomedicines with integrated multifunctionality."

Journal • Breast Cancer • Oncology • Solid Tumor

Combining Type I&II Photosensitizer With Hypoxia-Activated Prodrug Enables Oxygen-Unrestricted Synergistic Photocatalytic Therapy. (PubMed, Small) - "In vivo, DT@TH302 exhibits excellent biosafety and tumor-targeting capability, resulting in significant tumor growth suppression. This work provides an oxygen-unrestricted synergistic strategy to compensate for the limitations of standalone Type II PSs or HAPs monotherapy, offering valuable insights for clinical cancer treatment."

Journal • Metabolic Disorders • Oncology

Nucleophilic Selectivities of aliphatic electrophiles for Swain-Scott analysis: Fully protic and aqueous, green media, including hypoxia, and non-nucleophilic solvents | Poster Board #1680 (ACS-Fall 2026) - "Study of bendamustine showed rapid NBP alkylation and an s = 0.74 which we reported in 2018. Study of evofosfamide (TH-302) showed dramatic increases in NBP alkylation under anoxic conditions but with low s = 0.57 and low aerobic 6.5% alkylating activity (AA) vs. bis-(2-chloroethyl)amine (nor-HN2)(s = 0.98)...Extent of AA has been found predictive of dosing of ethyleneimines, from chlorambucil and mechlorethamine through the oxazaphosphoramines, cyclophosphamide and ifosfamide. Melflufen showed evidence of slow biphasic NBP alkylation consistent with peptide hydrolysis."

Molecular understanding for therapeutic targeting of hypoxia in breast cancer. (PubMed, Expert Opin Ther Targets) - "Apart HIF itself, other potential molecular targets such as prolyl-hydroxylases (PHD), von Hippel-Lindau protein (VHL), monocarboxylate transporters (MCTs), Na+ /H+ exchangers (NHEs), vacuolar ATPases (V-ATPase), anion exchangers (AEs), Na+ /HCO₃- co-transporters (NBCs), vascular endothelial growth factor (VEGF) and carbonic anhydrases were identified as being involved in tumorigenesis. HIF-1α inhibitors (topotecan, digoxin, PX-478), hypoxia-activated prodrugs (evofosfamide, apaziquone, porfiromycin, tirapazamine, banoxantrone) and carbonic anhydrase IX/XII inhibitors (SLC-0111) are either used clinically or in clinical development for the management of hypoxic breast cancers."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • Von Hippel-Lindau Syndrome • CA9 • HIF1A

Lactylation of HIF-1α at K172 drives HIF-1 complex assembly to promote hypoxia-induced immune evasion in esophageal squamous cell carcinoma. (PubMed, Cancer Lett) - "Functionally, reducing hypoxia with the agents TH-302 or PX-478 in the AKR model enhanced intratumoral CD8+ T cell infiltration and increased their expression of Granzyme B, IFNγ, and TNFα. Furthermore, in a preclinical ESCC model, pharmacological inhibition of HIF-1α with PX-478 synergized with anti-PD-1 therapy, leading to superior tumor control and enhanced CD8+ T cell cytotoxicity. Our study identifies HIF-1α K172 lactylation as a pivotal mechanism of hypoxia-mediated immune escape in ESCC, suggesting a therapeutic strategy to improve immunotherapy."

IO biomarker • Journal • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CD8 • GZMB • HIF1A • IFNG • TNFA

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

[18F]-FMISO-PET imaging to characterize the impact of obesity on the hypoxic tumor microenvironment during immunotherapy (AACR 2026) - "[18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) can non-invasively quantify hypoxia, allowing for patient stratification by hypoxia levels to predict IMT response and inform the use of secondary hypoxia-activated prodrugs, like evofosfamide (EVO). C57/Bl6J mice were fed a high-fat diet (HFD, n=68) or low-fat diet (LFD, n=19) for 13 weeks prior to E0771 implantation in the 3rd mammary fat pad on day -12... Our study supports ongoing literature demonstrating increased hypoxia in tumors in a HFD environment and that [18F]-FMISO stratification predicted response to immunotherapy in a TNBC model. Previous studies showed that lean tumor models have additive response when adding EVO to IMT in hypoxic tumors; however, our study demonstrated that EVO reduces hypoxia in hypoxic, obese tumors, but this did not salvage IMT response, likely due to increased tumorigenic immune changes."

Biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Targeted and molecular therapies in Ewing sarcoma: a comprehensive review of preclinical and clinical advances. (PubMed, Clin Transl Oncol) - "Targeted and molecular therapies in EWS show significant promise, particularly in rational combinations that exploit the tumor's dependence on EWS-FLI1-driven transcriptional dysregulation, DNA damage repair deficiencies, or survival signaling. Future research must prioritize biomarker-driven patient selection, integration of multiomics approaches, and multicenter prospective trials to translate these strategies into clinically meaningful improvements in EWS survival."

IO biomarker • Journal • Preclinical • Review • Ewing Sarcoma • Gene Therapies • Oncology • Sarcoma • Solid Tumor • AURKA • CD99 • EWSR1 • FLI1

Structural properties of antioxidant peptides released from sweet apricot kernel protein with regulation by ultrasound-assisted enzymolysis. (PubMed, Ultrason Sonochem) - "Molecular docking simulation indicates that the differential active pockets of Alcalase, Flavourzyme, Neutrase and Papain in traditional enzymolysis are Asp30-Gly102-Pro108-Ser109-Ser116-Tyr119-Gly131-Thr139-Asn144-Arg150-Lys151-Asn152-Asp153-Glu163-Asn166-Lys281-Ser324-Ser326-Pro425-Thr427, Gln91-Lys99-Ser248-Lys255-Val285-Glu287-Ala299-Cys301-Tyr325-Asn337-Gln359-Arg362, Ser49-Tyr107-Ser119-Val140-Asn152-Tyr194-Lys220-Arg221-Asn228 and Gly23-Arg111-Gln128-Asn155-Tyr208-Pro209 residues, respectively. Similarly, the correspondingly differential active pockets for ultrasound-assisted enzymolysis are Gly164-Ala172-Tyr195-Phe240-Asn383-Arg396, BMA3-Man4-Asp27-Tyr29-Glu43-Lys54-Glu61-Lys118-Ser153-Asp183-Ser186-Asp286-Asp298-Thr302-Thr305-Asp307-Ser339-Asp346, Glu167-Ser223 and Asp6-Gly20-Gys22-Arg58-Gln92-Gln114-Ala126-Lys156 residues, respectively. As a result, this investigation proves that ultrasound selectively increases cleavage sites of enzymolysis and the targeted..."

Journal • PLK4

EVO: Clinical Trial to Test Efficacy of Targeting Hypoxia Combined With ARSI After First-line ARSI Therapy for Castrate Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=35 | Not yet recruiting | Sponsor: University Health Network, Toronto | Trial completion date: Apr 2029 ➔ May 2030 | Initiation date: Apr 2025 ➔ May 2026 | Trial primary completion date: Apr 2027 ➔ May 2028

Trial completion date • Trial initiation date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Engineered macrophage membrane-mimicking nanodrugs activate cGAS/STING pathway to reverse tumor immune suppression after incomplete radiofrequency ablation. (PubMed, J Nanobiotechnology) - "To address these issues, this study engineered copper-doped ZIF-8 nanoparticles that co-deliver the hypoxia-activated prodrug TH-302 and the NQO1-targeting quinone β-lapachone, encapsulated within genetically engineered M1 macrophage membranes overexpressing CCR2 (CCR2-M)...No drug-related toxicity was observed. Thus, this rationally designed nanotherapeutic strategy significantly curtails residual tumor growth and offers a promising immunomodulatory approach to overcoming therapeutic resistance in cancer treatment after iRFA."

Journal • Oncology • Thermal Injury • CCL2 • CCR2 • CD8 • NQO1

A mathematical framework to optimize combination therapy for triple-negative breast cancer in obese mice (SABCS 2025) - "However, obesity-driven intratumoral hypoxia presents additional challenges for treatment, motivating the use of evofosfamide (a hypoxia-activated prodrug) as a therapeutic adjunct...The optimized schedules point to the possibility of achieving significantly better tumor control with less total drug dose, potentially translating into reduced toxicity while preserving benefit. These optimized regimens should be regarded as hypothesis-generating; their safety and therapeutic benefit must be experimentally confirmed."

Combination therapy • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Self-amplifying hypoxia cascade in covalent organic framework/metal organic framework nanoreactors for synergistic cancer therapy. (PubMed, J Colloid Interface Sci) - "Hypoxia-activated prodrugs (HAPs) like TH-302 exploit this niche, yet their efficacy is often limited by insufficient hypoxia levels...This coordinated action of chemodynamic therapy, photothermal therapy, PDT, and hypoxia-activated chemotherapy resulted in effective tumor suppression both in vitro and in vivo with minimal systemic toxicity. This work presents a novel strategy for leveraging the TME to achieve self-enhanced synergistic therapy."

Journal • Oncology

Hypoxia reduction remodels the glioblastoma immune microenvironment to enhance therapeutic sensitivity (SNO 2025) - "Together, these findings establish hypoxia as a central regulator of immune suppression in GBM and validate hypoxia-targeting strategies as powerful adjuncts to immunotherapy. Evofosfamide emerges as a potent immunomodulatory agent capable of reprogramming the GBM TME and unlocking new avenues for therapeutic intervention."

IO biomarker • Brain Cancer • Glioblastoma • Glioma • Solid Tumor • CD8 • CD80 • GZMB • HAVCR2 • LAG3 • PD-L1

Hypoxia reduction remodels the glioblastoma immune microenvironment to enhance therapeutic sensitivity (SNO 2025) - "Together, these findings establish hypoxia as a central regulator of immune suppression in GBM and validate hypoxia-targeting strategies as powerful adjuncts to immunotherapy. Evofosfamide emerges as a potent immunomodulatory agent capable of reprogramming the GBM TME and unlocking new avenues for therapeutic intervention."

IO biomarker • Brain Cancer • Glioblastoma • Glioma • Solid Tumor • CD8 • CD80 • GZMB • HAVCR2 • LAG3 • PD-L1

Hypoxia reduction remodels the glioblastoma immune microenvironment to enhance therapeutic sensitivity (WFNOS 2025) - "Together, these findings establish hypoxia as a central regulator of immune suppression in GBM and validate hypoxia-targeting strategies as powerful adjuncts to immunotherapy. Evofosfamide emerges as a potent immunomodulatory agent capable of reprogramming the GBM TME and unlocking new avenues for therapeutic intervention."

IO biomarker • Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor • CD8 • CD80 • GZMB • HAVCR2 • LAG3 • PD-L1

Hypoxia reduction remodels the glioblastoma immune microenvironment to enhance therapeutic sensitivity (WFNOS 2025) - P2 | "Together, these findings establish hypoxia as a central regulator of immune suppression in GBM and validate hypoxia-targeting strategies as powerful adjuncts to immunotherapy. Evofosfamide emerges as a potent immunomodulatory agent capable of reprogramming the GBM TME and unlocking new avenues for therapeutic intervention."

IO biomarker • Brain Cancer • Glioblastoma • Solid Tumor • CD8 • CD80 • GZMB • HAVCR2 • LAG3 • PD-L1

Development of hypoxia-activated prodrugs of AMPK inhibitors and evaluation in acute myeloid leukemia (AACR-NCI-EORTC 2025) - "Several HAPs have been developed, including Evofosfamide (TH-302) and Tarloxotinib (TH-4000), that utilize a nitroimidazole trigger that can be bioreduced under hypoxic conditions to release the active agent. In addition, we evaluated cellular target engagement in the MOLM-13 cell line by monitoring the phosphorylation of acetyl-CoA carboxylase (ACC) at Ser79 under both normal and hypoxic culture conditions. The development of HAPs of AMPK inhibitors have the potential to selectively sensitize drug resistant LSC to standard of care therapy or eliminate metabolically vulnerable LSCs as a single agent therapy."

Late-breaking abstract • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AMPK

Bimodality imaging as a companion to evaluate antitumour efficacy of TH-302 in experimental chondrosarcoma. (PubMed, EJNMMI Res) - "TH-302 shows an in vivo anti-tumour activity in chondrosarcoma. Our multimodal imaging approach allows monitoring complex exchanges between tumour cells and their neighboring under therapy."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • SLC2A1

Spatiotemporally Ultrasound-Activatable Self-Amplifying Biomimetic Liposomes for Imaging-Guided Synergistic Cancer Sonodynamic Chemotherapy. (PubMed, Nano Lett) - "Herein, we develop a biomimetic liposomal platform (DiR-VT@cmLipo) coencapsulating the sonosensitizer verteporfin (VP) and hypoxia-activated prodrug evofosfamide (TH302), which synergistically inhibits tumor progression via fluorescence imaging-guided ultrasound-activated spatiotemporally selective sonodynamic-chemotherapy. This biomimetic nanoplatform represents an innovative strategy for overcoming microenvironmental limitations in SDT, establishing a paradigm for synergistic tumor microenvironment remodeling and precision-controlled combination therapy. The cascaded self-amplifying activation mechanism and spatiotemporally tumor-selective therapeutic amplification position DiR-VT@cmLipo as a promising candidate for clinical translation in solid tumor management."

Journal • Oncology • Solid Tumor

Multifunctional nanoliposome-loaded hypoxia-activated evofosfamide: improving antitumor activity and ferroptosis in pancreatic adenocarcinoma. (PubMed, Int J Pharm) - "The EFA can be activated by reductase in cancer cell lines under a hypoxic milieu, which diminishes free radicals through the reductase enzyme and disrupts the adjacent biomacromolecules' structure, thereby facilitating the synergistic therapy of chemotherapy and ferroptosis in Panc-1 cells. This study integrates improved ferroptosis with hypoxia-activated chemotherapy to generate an effective and targeted tumoricidal impact, perhaps offering a promising treatment for pancreatic adenocarcinoma (PDAC) in the future."

Journal • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Evofosfamide Enhances Sensitivity of Breast Cancer Cells to Apoptosis and Natural-Killer-Cell-Mediated Cytotoxicity Under Hypoxic Conditions. (PubMed, Cancers (Basel)) - "Evofosfamide is converted into bromo-isophosphoramide mustard, a potent DNA cross-linking agent that is expected to enhance the killing of cancer cells under hypoxic conditions, where these cells typically exhibit resistance. qPCR analysis revealed that Evofosfamide was capable of restoring type I interferon signaling in hypoxic breast cancer cells, leading to the subsequent cytolytic activity of NK cells against the tumor cells. Thus, conditioning the breast cancer cells with Evofosfamide resulted in enhanced cell killing under hypoxia, further underscoring its potential as a sensitizer to target hypoxia-driven tumors."

Journal • Breast Cancer • Oncology • Solid Tumor • CASP3 • CASP7

Evofosfamide Enhances Sensitivity of Breast Cancer Cells to Apoptosis and Natural-Killer-Cell-Mediated Cytotoxicity Under Hypoxic Conditions (Multidisciplinary Digital Publishing Institute) - "Evofosfamide enhanced cell killing in both MCF-7 and MDA-MB-231 cells under hypoxic conditions compared to normoxic conditions. Cell killing was accompanied by increased cellular reactive oxygen species (ROS), diminished mitochondrial membrane potential, and induction of apoptosis, as demonstrated by the fragmentation or laddering of genomic DNA, the activation of caspase 3/7, and the cleavage of PARP."

Preclinical • Breast Cancer

TH-302 (evofosfamide) monotherapy exerts anticancer activity in Ewing's sarcoma cells under hypoxia. (PubMed, Clin Transl Oncol) - "These in vitro findings suggest that TH-302 may be efficacious in ES. This provides a rationale for further in vivo investigations into the potential of TH-302 as a treatment for ES."

Journal • Monotherapy • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • CASP3 • CASP7

Amplifying Anti-Tumor Immune Responses via Mitochondria-Targeting Near-Infrared Photodynamic Therapy. (PubMed, Adv Sci (Weinh)) - "Simultaneously, the exacerbated hypoxia induced by PDT activates a TH302 prodrug, resulting in cell cycle arrest in highly proliferative tumor cells...Moreover, the NIR-PDT-induced immune activation markedly improves the immune checkpoint blockade (ICB) therapy efficacy. This strategy offers a robust modality for immune activation in cancer therapy, paving the way for effective treatment of deep-seated tumors and preventing recurrence."

Journal • Liver Cancer • Oncology • Solid Tumor