AZD-3965 / Cancer Research UK - LARVOL DELTA

PRL-3 enhances multiple myeloma cell survival in acidic microenvironments via metabolic adaptation and pH regulation. (ASH 2025) - "Pharmacologic inhibition of lactate and proton transport was performed using Syrosingopine (dualMCT inhibitor), AZD0095 (MCT4 inhibitor), AZD3965 (MCT1 inhibitor), Bafilomycin A1 (v-ATPase inhibitor),and ethyl isopropyl amiloride (EIPA; NHE1 inhibitor). Thissuggests compensatory roles among transporters and pathways whose importance varies depending onthe pH level. Increased metabolism and proton transport are associated with high PRL-3 expression,supporting PRL-3 as a key protein for cell survival in acidic conditions and a potential therapeutic targetin myeloma treatment."

Hematological Malignancies • Multiple Myeloma • ANXA5 • PTP4A3 • SLC16A1

Monocarboxylate transporter 1 deficient donor T cells rewire metabolism and ameliorate aGVHD lethality (ASH 2025) - "Despite fewer effector T cells,lower cytolytic molecule expression, and a higher Treg frequency, under aGVHD conditions, MCT1 KOdonor T cells effectively cleared A20-luciferase+ lymphoma cells for 30 days with a 75 percent survivalrate, in contrast to uniform aGVHD lethality in WT mice that died without evidence of tumor cells.ConclusionsThese findings underscore an obligate role of MCT1in alloreactive T cell responses and its divergenteffects on alloreactive effector versus central memory and Treg subsets. Targeting MCT1 with inhibitorsincluding AZD3965 may represent a novel therapeutic strategy to mitigate aGVHD without abrogation ofgraft-versus-tumor effects."

IO biomarker • Acute Graft versus Host Disease • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immunology • Lymphoma • CCR7 • CD4 • ENTPD1 • FOXP3 • GZMA • GZMB • ICOS • IL2RA • LAG3 • LDHA • PD-1 • SLC16A1

A non-canonical glycolytic endpoint supports HSC survival and function (ASH 2025) - "Transplant recipients of Ldha; Ldhb and Ldha/Ldhb/Pdha1 bonemarrow cells treated with AZD3965, an MCT1 inhibitor, exhibited impaired HSC function. a) Suggest that glycolytic lactate production is not essential in HSCs in contrast to the idea thatHSCs are glycolytic; b) Reveal metabolic plasticity that sustains HSC survival and function independent ofcanonical glycolytic endpoints; and c) Most fundamentally, they redefine how glucose can be catabolizedin vivo by showing that the canonical endpoints of glycolysis are dispensable for metabolism and cellfunction."

Hematological Disorders • CD48 • LDHA • LDHB • PDHA1 • SLC16A1

N-acetylcysteine induced lactate reprogramming is a targetable metabolic susceptibility in glioblastoma. (SNO 2025) - "To test the effects of lowering lactate levels on NAC-induced cytotoxicity, we treated glioma cells with the mitochondrial pyruvate dehydrogenase enzyme complex inhibitor dichloroacetate (DCA)...Blocking lactate import/export via inhibition of MCT transporters (AZD3965 and Syrosingopine) significantly enhances NAC-induced cytotoxicity...Our data suggests that lactate reprogramming is a targetable susceptibility of NAC treatment. The unique sensitivity of GBM towards NAC and its dependence on lactate as an oncometabolite governing metabolic resistance might open a novel druggable pathway for treating both IDHwt and IDHmut gliomas."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • LDHA

N-acetylcysteine induced lactate reprogramming is a targetable metabolic susceptibility in glioblastoma. (SNO 2025) - "To test the effects of lowering lactate levels on NAC-induced cytotoxicity, we treated glioma cells with the mitochondrial pyruvate dehydrogenase enzyme complex inhibitor dichloroacetate (DCA)...Blocking lactate import/export via inhibition of MCT transporters (AZD3965 and Syrosingopine) significantly enhances NAC-induced cytotoxicity...Our data suggests that lactate reprogramming is a targetable susceptibility of NAC treatment. The unique sensitivity of GBM towards NAC and its dependence on lactate as an oncometabolite governing metabolic resistance might open a novel druggable pathway for treating both IDHwt and IDHmut gliomas."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • LDHA

FiLactate-Induced Lysine Lactylation: A Central Node Linking Metabolic Rewiring, Epigenetic Plasticity and Therapeutic Vulnerabilities in Hepatocellular Carcinoma. (PubMed, J Biochem Mol Toxicol) - "A Kla-high transcriptional signature shortens median overall survival by 18 months and stratifies patients with poor response to sorafenib and immune checkpoint blockade. Three convergent therapeutic entry points emerge: depletion of lactate via glycolytic inhibition or MCT1/4 blockade (FX11, AZD3965), enzymatic modulation of Kla writers or erasers, and PROTAC-mediated degradation of oncogenic lactylated proteins. In murine and patient-derived xenograft models, these strategies reduce tumour volume by at least 50% and synergise durably with anti-PD-1 therapy. This integrated synthesis positions lysine lactylation as a hierarchical regulator that links metabolic stress to epigenetic plasticity, immune escape, and therapeutic vulnerability, and outlines a biomarker-driven roadmap for lactylation-targeted precision medicine in HCC."

IO biomarker • Journal • Review • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ALDOA • CTNNB1 • MYC • STAT3

N-acetylcysteine induced lactate reprogramming is a targetable metabolic susceptibility in glioblastoma. (WFNOS 2025) - "To test the effects of lowering lactate levels on NAC-induced cytotoxicity, we treated glioma cells with the mitochondrial pyruvate dehydrogenase enzyme complex inhibitor dichloroacetate (DCA)...Blocking lactate import/export via inhibition of MCT transporters (AZD3965 and Syrosingopine) significantly enhances NAC-induced cytotoxicity...Our data suggests that lactate reprogramming is a targetable susceptibility of NAC treatment. The unique sensitivity of GBM towards NAC and its dependence on lactate as an oncometabolite governing metabolic resistance might open a novel druggable pathway for treating both IDHwt and IDHmut gliomas."

Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • LDHA

N-acetylcysteine induced lactate reprogramming is a targetable metabolic susceptibility in glioblastoma. (WFNOS 2025) - "To test the effects of lowering lactate levels on NAC-induced cytotoxicity, we treated glioma cells with the mitochondrial pyruvate dehydrogenase enzyme complex inhibitor dichloroacetate (DCA)...Blocking lactate import/export via inhibition of MCT transporters (AZD3965 and Syrosingopine) significantly enhances NAC-induced cytotoxicity...Our data suggests that lactate reprogramming is a targetable susceptibility of NAC treatment. The unique sensitivity of GBM towards NAC and its dependence on lactate as an oncometabolite governing metabolic resistance might open a novel druggable pathway for treating both IDHwt and IDHmut gliomas."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • LDHA

Histone H4K8 lactylation modulated immunosuppressive properties by promoting FAP transcription and ECM remodeling. (PubMed, Gastric Cancer) - "We elucidate a Kla-dependent mechanism underlying GCMSCs-mediated ECM remodeling and immunosuppressive niche formation. The results provide novel insights into the epigenetic regulation of immunosuppressive TME."

Journal • Gastric Cancer • Oncology • Solid Tumor • AARS1 • CD8

Elucidating the Role of Tolerogenic Dendritic Cells in Immune Tolerance and Disease Progression in Multiple Myeloma (ASH 2023) - "Treatment with AZD3965 improved the phenotype of moDCs co-cultured with MM cells, reversing their suppressive effect on T-cell proliferation... Patients with MM exhibit a reduced frequency of cDC1 subsets, which are crucial for cross-presentation to CD8 + T cells. moDCs in acid pH conditions derived from MM cells display an immature phenotype and impaired function due to decreased DC activation signals. Furthermore, inflammasome activation promotes the secretion of IL-1β and IL-18, contributing to pro-tumorigenic inflammation in the MM microenvironment."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CD14 • CD1C • CD73 • CD8 • CD80 • CD83 • CD86 • CDK1 • CSF2 • IFNG • IL10 • IL18 • IL1B • IL4 • ITGAX • NOS2 • SLC16A1

Lactate Transporters Modulate Stromal Cell Remodeling in Myeloproliferative Neoplasms (MPN) (ASH 2023) - "Since PMF patients showed an increased percentage of circulating immunosuppressive cells such as G- and M-MDSC and Treg, we incubated healthy peripheral blood mononucleated cells (PBMNCs) with PMF sera in the presence or absence of MCT1inhibitor (AZD3965) to evaluate the role of lactate in the expansion of these immunological subsets...Inhibition of lactate metabolism may represent a strategy to inhibit cancer cells and contribute to restoring the anti-cancer immune response. Therefore, lactate metabolism may represent a promising target to counteract inflammation, osteosclerosis, and fibrosis in PMF patients."

Stroma • Essential Thrombocythemia • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis • CD34 • MMP2 • MMP9 • TGFB1 • TNFRSF11B

4-Octyl Itaconate Promotes Diabetic Wound Healing by Enhancing Pro-Resolving Macrophages via the Efferocytosis-MCT1-Lactate-GPR132 Pathway and Macrophage-Independent Synergistic Effects. (PubMed, Diabetes Metab J) - "To further evaluate the roles of macrophages, monocarboxylate transporter 1 (MCT1), and lactate in 4-OI-promoted diabetic wound healing, we used clodronate-liposomes (CLD-Lipo) to deplete macrophages, AZD3965 (an MCT1 inhibitors), telmisartan to validate our hypothesis. 4-OI promotes diabetic wound healing through macrophage-dependent/independent mechanisms. Moreover, the protective effect of 4-OI on macrophage was mediated through MCT1-mediated lactate release triggered by efferocytosis and subsequent GRP132 activation."

Journal • Diabetes • Metabolic Disorders • GPR132 • SLC16A1

Role of monocarboxylate transporters in cancer immunology and their therapeutic potential. (PubMed, Br J Pharmacol) - "Combinational therapy using MCT1 inhibitors (e.g. AZD3965), MCT4 inhibitors and immune checkpoint blockade can suppress lactate-mediated immunosuppression in the TME. By disrupting lactate shuttling between glycolytic and oxidative tumour cells, this strategy promotes T cell function and improves cancer treatment outcomes."

IO biomarker • Journal • Review • Oncology • SLC16A1

Jing An decoction alleviates neuroinflammation in Tourette syndrome by regulating butyrate-mediated microbiota-gut-brain axis. (PubMed, Phytomedicine) - "JA alleviates TS by regulating the GBA axis through butyrate-producing bacteria. Butyrate alleviates neuroinflammation by inhibiting the TLR4/HDAC3/NF-κB pathway, thereby promoting M2 microglial polarization."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Inflammation • Movement Disorders • Psychiatry • Tourette Syndrome • HDAC3

Mitochondrial fission factor drives an actionable metabolic vulnerability in multiple myeloma. (PubMed, Haematologica) - "Finally, we highlight a novel lactate-MFF axis involved in proteasome inhibitor resistance, and show that combining AZD3965 or Syrosingopine with bortezomib results in synergistic anti-MM activity along with MFF down-regulation. Collectively, these data point to MFF-dependent mitochondrial fragmentation as a key metabolic hallmark of MM, providing a framework for the development of novel therapeutic strategies targeting mitochondrial dynamics and harnessing the metabolic plasticity of malignant plasma cells."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Lactate induces oxidative phosphorylation in osteoblasts via Gpr81-Stat3 signaling. (PubMed, Cell Signal) - "Inhibition of Gpr81 by 3-OBA or decrease in Gpr81 expression by Gpr81 siRNA, but not the interruption of MCT1 by AZD3965, led to the inhibition of the Gpr81-Jak2-Stat3-Y705 and Gpr81-Akt-Stat3-S727 signaling, and OXPHOS and cell differentiation of MC3T3-E1 cells were also inhibited...Lastly, osteoblast GPR81-deficient mice showed lower bone formation. Thus, these findings propose a novel signaling mechanism by which lactate regulates cell differentiation as well as OXPHOS through the activation of Stat3 signaling by Gpr81."

Journal

Lactate facilitates pancreatic repair following acute pancreatitis by promoting reparative macrophage polarization. (PubMed, Cell Mol Gastroenterol Hepatol) - "Lactate facilitates pancreatic repair by promoting reparative macrophage polarization, achieved through promoting lactylation and inhibiting JAK2-STAT1 signaling. This phenotypic shift alleviates inflammation and facilitates tissue recovery, highlighting a potential therapeutic approach for AP."

Journal • Inflammation • Pancreatitis • GPR132 • PFKFB3

Gastric cancer cells shuttle lactate to induce inflammatory CAF-like phenotype and function in bone marrow-derived mesenchymal stem cells. (PubMed, Mol Immunol) - "Herein, exogenous lactate induced a pro-tumorigenic phenotype in BM-MSCs, which was blocked by AZD3965...Collectively, gastric cancer cells induce an iCAF-like phenotype and function in BM-MSCs through a lactate shuttle mechanism, emphasizing the role of metabolic reprogramming in cellular communication that fosters a supportive tumor microenvironment. Targeting lactate-related pathways may provide new therapeutic strategies to hinder BM-MSCs' supportive roles in gastric cancer."

Journal • Gastric Cancer • Hematological Malignancies • Oncology • Solid Tumor • CAFs • CD8 • CXCL8 • PD-L1 • TGFB1

Tumor cell oxidative metabolism triggers immune escape in advanced kidney cancer (IMMUNOLOGY 2025) - "Furthermore, treating mice with an MCT1 inhibitor (AZD3965) rescued responsiveness to anti-PD-L1 therapy, identifying a novel clinical axis to bolster cancer treatments. In conclusion, this study uncovers a previously underappreciated role for cancer-oxidative metabolism in driving immune evasion and disease progression, identifies its underlying biological mechanisms, and proposes MCT1 inhibition as a promising therapeutic avenue for high risk ccRCC patients.Keywords: Animals Human Rodent; Cells T Cells; Processes Cell Differentiation Cytotoxicity"

Metastases • Tumor cell • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD8

LACTATE FACILITATES PANCREATIC REPAIR FOLLOWING ACUTE PANCREATITIS BY PROMOTING REPARATIVE MACROPHAGE POLARIZATION (DDW 2025) - "Treatment with AZD3965, a chemical inhibitor of lactate transportation, blocked the effects on lactylation and gene expression... Lactate facilitates pancreatic repair by promoting reparative macrophage polarization, achieved through promoting lactylation and inhibiting JAK2-STAT1 signaling via GPR132. This phenotypic shift alleviates inflammation and facilitates tissue recovery, highlighting a potential therapeutic approach for AP. Keywords : lactate; acute pancreatitis; pancreatic repair; macrophage; lactylation"

Inflammation • Pancreatitis • GPR132 • HMGB1 • LDHA • LRG1 • PFKFB3

Cr (VI) induces lactate utilization through HIF-1α/MCT1 dependent on p53 protein level. (PubMed, Food Chem Toxicol) - "CoCl2, an HIF-1α inducer, increased MCT1, while the HIF-1α inhibitor YC-1 and MCT1 inhibitor AZD3965 suppressed Cr (VI)-induced lactate utilization and cell growth...These findings highlighted the role of p53 protein level in the effects of Cr (VI) on HIF-1α/MCT1 to induce lactate utilization and cell growth. Targeting the p53/HIF-1α/MCT1 pathway could inhibit Cr (VI)-mediated tumorigenesis."

Journal • Oncology • HIF1A • SLC16A1

Impact of MCT1 inhibition on NSCLC metabolism and sensitivity to therapy (AACR 2025) - "AZD3965 did not confer additional cytotoxic effect to cells treated with paclitaxel. MCT1 inhibition decreases lactate import and oxidation in vitro and causes DNA damage to enhance the cytotoxic effects of pemetrexed. MCT1 inhibition decreases lactate import and oxidation in vitro and causes DNA damage to enhance the cytotoxic effects of pemetrexed. Metabolic reprogramming in NSCLC leads to the use of alternate carbon sources, such as lactate, and this can be modeled in both standard and physiologic culture conditions. Notably, this does not appear to be a general sensitization to cell death."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ANXA5 • SLC16A1

Lactic acid inhibits the interaction between PD-L1 protein and PD-L1 antibody in the PD-1/PD-L1 blockade therapy-resistant tumor. (PubMed, Mol Ther) - "Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the monocarboxylate transporter 1 (MCT-1) inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade-resistant tumors. The findings of this study provide a new mechanism of how lactic acid induces an immunosuppressive tumor microenvironment and suggest a potential combination treatment to overcome the tumor resistance to PD-1/PD-L1 blockade therapy."

Journal • Oncology • SLC16A1

The role of tumor microenvironment lactic acid in the cancer cell resistance to anti-PD-L1 and anti-PD-1 blockade therapy (AACR 2025) - "Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. Altogether, the findings in this study uncover a new mechanism of how lactic acid induces an immunosuppressive tumor microenvironment and suggest a potential combination treatment strategy to overcome the tumor resistance to PD-1/PD-L1 blockade therapy and improve clinical outcomes."

Biomarker • Tumor microenvironment • Oncology

MCT1 regulates the progression of early invasive oral squamous cell carcinoma (AACR 2025) - "An MCT1 inhibitor, AZD3965, was used to assess invasion in OTCs and disease progression in a mouse model of oral carcinogenesis...Our data also suggest potential metabolic vulnerabilities in oral cancer cells can be exploited by targeting cholesterol and lipid synthesis pathways in combination with MCT1 inhibition. Our ongoing work involves further assessment of mechanisms regulated by MCT1 to promote progression of oral cancer, including ATAC-seq to assess epigenetic changes, metabolite analysis and metabolic tracing, and the development of relevant mouse models."

Late-breaking abstract • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • SLC16A1