AZD-3965 / Cancer Research UK - LARVOL DELTA

Subcellular localization heterogeneity of MCT1 remodels the exhausted immune microenvironment and effects therapeutic responses in bladder urothelial carcinoma (ECP 2026) - "Crucially, ex vivo PTC assays uncovered divergent therapeutic susceptibilities: MC-type PTCs were profoundly sensitive to anti-PD-1 therapies (Pembrolizumab/Toripalimab), with killing rates reaching 100% accompanied by elevated IL-8, whereas N-type PTCs exhibited ICB resistance but were significantly more sensitive to specific MCT1 inhibitors, notably AZD3965. The subcellular spatial heterogeneity of MCT1 drives immune exhaustion and defines distinct TME phenotypes in BLCA. The MCT1 spatial profiling provides a highly translational paradigm for predicting ICB efficacy and guiding precision targeted therapies."

Heterogeneity • IO biomarker • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer • CD8 • CTLA4 • CXCL8 • PD-L1 • SLC16A1 • SLC16A4 • TIGIT

Lactic acid exposure alters lysophosphatidic acid receptor-mediated regulation of growth and motility in pancreatic cancer cells. (PubMed, Mol Cell Biochem) - "PANC-LA5 cell growth and PANC-LA1 cell motility were inhibited by AZD3965 and galloflavin. These findings indicate that LPA receptor signaling is involved in the regulation of PANC-1 cell behavior induced by long-term lactic acid exposure, with LPA1 and LPA3 acting as major positive regulators of proliferation and motility following long-term lactic acid exposure, whereas LPA2 and LPA5 exert distinct regulatory effects."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • LPAR3 • LPAR5

AlCl3 Aerosol Exposure Is Associated With Pulmonary Lactate Accumulation, Neutrophil Dysfunction, and Fibrosis-Like Remodeling. (PubMed, Biofactors) - "Rats were subjected to repeated AlCl3 aerosol exposure with or without pharmacological inhibition of lactate transport using the monocarboxylate transporter 1 inhibitor AZD3965...Pharmacological modulation of lactate transport provides supportive evidence for the involvement of lactate-associated metabolic regulation in this process, although further studies are required to define the specific molecular targets involved. The integration of experimental and supportive human findings suggests that the lactate-neutrophil dysfunction axis may represent a mechanistically relevant feature of aluminum-associated lung injury and remodeling."

Journal • Fibrosis • Immunology • Inflammation • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • SLC16A1

Radiosynthesis and Preclinical Evaluation of Enantiopure (R)-[18F]Fluorolactate for PET Imaging of Metabolic Processes. (PubMed, Mol Pharm) - "The monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 significantly reduced tracer uptake in normal tissues and LLC tumors, and increased renal excretion, confirming MCT1-mediated transport...In silico structural analyses supported the experimental findings. (R)-[18F]Fluorolactate is a metabolically stable, MCT1-sensitive PET tracer suitable for noninvasive assessment of lactate transport and metabolism and shows promise for imaging MCT1-dependent lactate transport in cancer."

Journal • Preclinical • Lung Cancer • Metabolic Disorders • Oncology • Solid Tumor • SLC16A1

6-[18F]Fluoronicotinic Acid PET Visualizes Intracranial Human Glioblastoma Xenografts that are [18F]FET PET Negative (EACR 2026) - "In vivo blocking with AZD3965, a dual inhibitor of MCT1 and MCT2, reduced [18F]FNA tumor uptake by 68─77%, while blocking MCT4 reduced uptake by 23%. We could not visualize the human glioblastoma xenografts in mice by [18F]FET PET; However, tumor uptake was clearly observed with [18F]FNA and [11C]MET PET. We could not visualize the human glioblastoma xenografts in mice by [18F]FET PET; However, tumor uptake was clearly observed with [18F]FNA and [11C]MET PET. MCT1, MCT2, and MCT4 contribute substantially to [18F]FNA uptake in glioblastoma and other tissues. Thus, given its distinct biological uptake mechanism relative to current clinical tracers, [18F]FNA could be an alternative approach for clinical PET imaging of glioblastoma."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor

Phenylalanine Versus Tyrosine (Pos. 367/332 in MCT1/MCT4) in the Substrate Binding Site Defines Affinity and Preferred Directionality of Human Monocarboxylate Transporters 1-4. (PubMed, Acta Physiol (Oxf)) - "Together, subtle changes in the arrangement of sidechains in the MCT binding site determine basic monocarboxylate/H+ transport properties that impact lactate-related physiology, namely cellular metabolism, reprogramming, and signaling."

Journal • Oncology

Intracranial Human BT12 Glioblastoma Xenograft is [18F]FET PET Negative but 6-[18F]Fluoronicotinic Acid PET Positive: Exploring a Novel Approach for Clinical Glioblastoma Imaging. (PubMed, Mol Pharm) - "In vivo blocking with AZD3965, a dual inhibitor of MCT1 and MCT2, reduced [18F]FNA tumor uptake by 68-77%, while blocking MCT4 reduced uptake by 23%...MCT1, MCT2, and MCT4 have significant roles in [18F]FNA uptake in glioblastoma and other tissues. [18F]FNA could be an alternative approach for clinical PET imaging of glioblastoma based on a biological mechanism completely different from current clinical approaches."

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

Targeting Lactate-Driven Stromal Autophagy via MCT1 Disrupts the Immunosuppressive Niche and Sensitizes Pancreatic Cancer to PD-1 Blockade. (PubMed, Adv Sci (Weinh)) - "Notably, AZD3965, a specific MCT1 inhibitor, sensitizes orthotopic PC to PD-1 blockade, effectively inhibiting tumor development...Moreover, activated PSCs secrete CXCL9/CXCL10, which upregulates PD-1 expression in CD8+ T cells via the CXCR3/STAT3 pathway. This study establishes lactate as a crucial TME signaling molecule orchestrating PSC activation and an immunosuppressive microenvironment, providing compelling evidence for combining MCT1 inhibition with immune checkpoint blockade for pancreatic cancer."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • CXCL10 • CXCL9 • CXCR3

Lactylation landscape of mitochondrial proteins in myocardial infarction. (PubMed, Redox Biol) - "Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction...Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease."

Journal • Cardiovascular • Coronary Artery Disease • Fibrosis • Heart Failure • Immunology • Inflammation • Metabolic Disorders • Myocardial Infarction • SLC16A1

GPX8+ cancer-associated fibroblast-derived lactate contributes to lenvatinib resistance by facilitating BRPF1 expression through histone H3 lysine 18 lactylation in hepatocellular carcinoma. (PubMed, Oncogene) - "Pharmacological inhibition of MCT1 (AZD3965) or BRPF1 (GSK5959), effectively reversed lenvatinib resistance in vitro and in vivo. These findings establish the GPX8⁺ CAF/lactate/MCT1/H3K18la/BRPF1/EGFR axis as a pivotal driver of lenvatinib resistance and identify MCT1 and BRPF1 as actionable therapeutic targets for overcoming resistance in HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CAFs • GPX8 • SLC16A1

GPX8+ cancer-associated fibroblast-derived lactate contributes to lenvatinib resistance by facilitating BRPF1 expression through histone H3 lysine 18 lactylation in hepatocellular carcinoma (Nature) - "We demonstrate that GPX8 overexpression in CAFs activates the PI3K/AKT/mTOR signaling pathway by suppressing endoplasmic reticulum stress, driving glycolytic reprogramming and lactate production. HCC cells import this CAF-derived lactate via monocarboxylate transporter 1 (MCT1), elevating histone H3 lysine 18 lactylation (H3K18la) levels. Increased H3K18la enrichment at the promoter of bromodomain and PHD finger-containing protein 1 (BRPF1) transcriptionally upregulates BRPF1 expression....Pharmacological inhibition of MCT1 (AZD3965) or BRPF1 (GSK5959), effectively reversed lenvatinib resistance in vitro and in vivo."

Preclinical • Hepatocellular Cancer

Lactylation landscape of mitochondrial proteins in myocardial infarction. (PubMed, bioRxiv) - "Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease. Myocardial infarction (MI) increases mitochondrial protein lactylation, with 361 identified lactylated proteins.AZD3965-mediated MCT1 inhibition further elevates mitochondrial lactylation.Distinct alterations in mitochondrial proteins and pathways (TCA cycle, amino acid metabolism, gene expression) were observed.AZD3965 reduces cardiac fibrosis and inflammation and partly improves mitochondrial respiration post-MI, but cardiac function remains impaired."

Journal • Cardiovascular • Coronary Artery Disease • Fibrosis • Heart Failure • Immunology • Inflammation • Metabolic Disorders • Myocardial Infarction • SLC16A1

Triptolide alleviates rheumatoid arthritis by inhibiting lactate-mediated activation of mTORC1/HIF-1α to restrain Th17 cell differentiation. (PubMed, Int Immunopharmacol) - "TP alleviates RA symptoms by reducing lactate accumulation through downregulation of LDHA and MCT1, suppressing mTORC1/HIF-1α signaling, and disrupting its feedback activation, thereby inhibiting Th17 cell differentiation."

Journal • Immunology • Inflammatory Arthritis • Ophthalmology • Rheumatoid Arthritis • Rheumatology • CD4 • EIF4EBP1 • HIF1A • LDHA • 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

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 • SLC16A1

Lactate Facilitates the Survival and Invasion of Pancreatic Cancer Cells Under Glucose Deprivation. (PubMed, FASEB J) - "Importantly, the MCT1 inhibitor AZD3965 synergistically enhanced the anticancer effects of the glycolysis inhibitor 2-DG. Taken together, our results demonstrate that MCT1-mediated lactate influx sustains PC proliferation under glucose starvation, and combined inhibition of MCT1 and glycolysis could be leveraged for treatment of PC."

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

Lactate-mediated NK cell dysfunction as a prognostic marker and therapeutic target in breast cancer. (PubMed, Cell Death Discov) - "Pharmacologic inhibition of lactate transport, via Syrosingopine or MSC-4381 and AZD3965 combination, restored NK cell cytotoxicity in tumor co-cultures, as shown by increased NK cell degranulation, caspase-3/7-mediated tumor apoptosis, and spheroid shrinkage. Finally, GPR81 deletion mirrored these effects, enhancing NK cell activity. These findings identify lactate as a driver of NK cell suppression and highlight lactate transport and receptor targeting as a strategy to enhance NK cell-based immunotherapies in breast cancer and other lactate-rich tumors."

Biomarker • IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • CASP3 • CASP7 • CXCL10 • CXCL9

Combinatorial drug screen identifies therapeutic vulnerabilities of pancreatic cancer subtypes (ESMO-TAT 2026) - "decitabine, oxidative stress inducer elesclomol, and mitogen-activated protein kinase kinase (MEK) inh...rabusertib and AZD7762 ranked among the top combinations with AZD3965...adavosertib also sparked interest, as CHK1 and WEE1 inh... This systematic approach identifies candidate drug pairs for further preclinical testing and highlights translational starting points for developing personalized combination therapies to overcome resistance."

Colon Cancer • Colorectal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CHEK1 • SLC16A1

Prognostic Significance and Immune Landscape of Migrasome-Related Genes in Pancreatic Cancer. (PubMed, Appl Biochem Biotechnol) - "Drug sensitivity prediction and molecular docking indicated that the monocarboxylate transporter 1 (MCT1) inhibitor AZD-3965 may have therapeutic potential in this context. In general, our findings suggest that migrasome-related genes may contribute to prognostic stratification of pancreatic cancer and point to mechanisms of stroma-immune crosstalk, thereby offering exploratory avenues for personalized treatment."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • ITGA3 • ITGA5 • SLC16A1 • TSPAN2 • WNT11

Mechanisms of lactylation modification in hepatocellular carcinoma treatment resistance. (PubMed, Gastroenterol Rep (Oxf)) - "Key resistance pathways include: lactylated IGF2BP3 activating PCK2-NRF2 to counter lenvatinib-induced stress; ALDOA lactylation enhancing liver cancer stem cell self-renewal for chemoresistance; MOESIN lactylation in Regulatory T cells (Tregs) weakening anti-PD-1 efficacy. Therapeutically, 2-DG, AZD3965, or SIRT3 activators (reverse lactylation) restore drug sensitivity, alone or in combination. Despite limited specific detectors, lactylation is a promising target to overcome HCC drug resistance, aiding precision treatment."

IO biomarker • Journal • Review • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • ALDOA • IGF2BP3 • SIRT3

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