Lactate Efflux Research Articles

Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors.

The development of tumors relies on lactate metabolic reprogramming to facilitate their unchecked growth and evade immune surveillance. This poses a significant challenge to the efficacy of antitumor immunity. To address this, a tumor-selective nano-dispatcher, PIMDQ/Syro-RNP, to enforce the immunotherapeutic effect through regulation of lactate metabolism and activation of toll-like receptors is developed. By using the tumor-targeting properties of c-RGD, the system can effectively deliver monocarboxylate transporters 4 (MCT4) inhibitor (Syro) to inhibit lactate efflux in tumor cells, leading to decreased lactate levels in the tumor microenvironment (TME) and increased accumulation within tumor cells. The reduction of lactate in TME will reduce the nutritional support for regulatory T cells (Tregs) and promote the effector function of T cells. The accumulation of lactate in tumor cells will lead to tumor death due to cellular acidosis. In addition, it will also reduce the uptake of glucose by tumor cells, reduce nutrient plunder, and further weaken the inhibition of T cell function. Furthermore, the pH-responsive release of Toll-like receptors (TLR)7/8 agonist IMDQ within the TME activates dendritic cells (DCs) and promotes the infiltration of T cells. These findings offer a promising approach for enhancing tumor immune response through targeted metabolic interventions.

Mitochondrial-uncoupling nanomedicine for self-heating and immunometabolism regulation in cancer cells

Developing endogenous hyperthermia offers a promising strategy to address challenges with current exogenous hyperthermia techniques in clinics. Herein, a CD44-targeted and thermal-responsive nanocarrier was developed for the simultaneous delivery of 2,4-dinitrophenol and syrosingopine. The objective was to induce endogenous hyperthermia and regulate immunometabolism, ultimately augmenting anti-tumour immune responses. Dinitrophenol as mitochondrial uncoupler can convert electrochemical potential energy of inner mitochondrial membrane into heat, facilitating endogenous hyperthermia. Meanwhile, syrosingopine not only inhibits excessive lactate efflux caused by dinitrophenol but also downregulates tumour cell glycolysis, thus alleviating immunosuppression and heat shock protein (HSP)-dependent thermo-resistance through immunometabolism regulation. The synergistic effects of endogenous hyperthermia and immunometabolism regulation by this nanomedicine have potential to enhance tumor immunogenicity, reshape the tumour immune microenvironment, and effectively suppress the growth of subcutaneous tumours and patient-derived organoids in triple-negative breast cancer. Therefore, the endogenous hyperthermia strategy developed in this study would revolutionize hyperthermia for cancer treatment.

Harnessing the Power of Sugar-Based Nanoparticles: A Drug-Free Approach to Enhance Immune Checkpoint Inhibition against Glioblastoma and Pancreatic Cancer.

Cancer cells have a high demand for sugars and express diverse carbohydrate receptors, offering opportunities to improve delivery with multivalent glycopolymer materials. However, effectively delivering glycopolymers to tumors while inhibiting cancer cell activity, altering cellular metabolism, and reversing tumor-associated macrophage (TAM) polarization to overcome immunosuppression remains a challenging area of research due to the lack of reagents capable of simultaneously achieving these objectives. Here, the glycopolymer-like condensed nanoparticle (∼60 nm) was developed by a one-pot carbonization reaction with a single precursor, promoting multivalent interactions for the galactose-related receptors of the M2 macrophage (TAM) and thereby regulating the STAT3/NF-κB pathways. The subsequently induced M2-to-M1 transition was increased with the condensed level of glycopolymer-like nanoparticles. We found that the activation of the glycopolymer-like condensed galactose (CG) nanoparticles influenced monocarboxylate transporter 4 (MCT-4) function, which caused inhibited lactate efflux (similar to inhibitor effects) from cancer cells. Upon internalization via galactose-related endocytosis, CG NPs induced cellular reactive oxygen species (ROS), leading to dual functionalities of cancer cell death and M2-to-M1 macrophage polarization, thereby reducing the tumor's acidic microenvironment and immunosuppression. Blocking the nanoparticle-MCT-4 interaction with antibodies reduced their toxicity in glioblastoma (GBM) and affected macrophage polarization. In orthotopic GBM and pancreatic cancer models, the nanoparticles remodeled the tumor microenvironment from "cold" to "hot", enhancing the efficacy of anti-PD-L1/anti-PD-1 therapy by promoting macrophage polarization and activating cytotoxic T lymphocytes (CTLs) and dendritic cells (DCs). These findings suggest that glycopolymer-like nanoparticles hold promise as a galactose-elicited adjuvant for precise immunotherapy, particularly in targeting hard-to-treat cancers.

Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.

Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Metal-Coordinated NIR-II Nanoadjuvants with Nanobody Conjugation for Potentiating Immunotherapy by Tumor Metabolism Reprogramming.

Immune checkpoint blockade (ICB) immunotherapy remains hampered by insufficient immunogenicity and a high-lactate immunosuppressive tumor microenvironment (TME). Herein, a nanobody-engineered NIR-II nanoadjuvant with targeting metabolic reprogramming capability is constructed for potentiating NIR-II photothermal-ferroptosis immunotherapy. Specifically, the nanoadjuvant (2DG@FS-Nb) is prepared by metallic iron ion-mediated coordination self-assembly of D-A-D type NIR-II molecules and loading of glycolysis inhibitor, 2-deoxy-D-glucose (2DG), followed by modification with aPD-L1 nanobody (Nb), which can effectively target the immunosuppressive TME and trigger in situ immune checkpoint blockade. The nanoadjuvants responsively release therapeutic components in the acidic TME, enabling the precise tumor location by NIR-II fluorescence/photoacoustic imaging while initiating NIR-II photothermal-ferroptosis therapy. The remarkable NIR-II photothermal efficiency and elevated glutathione (GSH) depletion further sensitize ferroptosis to induce severe lipid peroxidation, provoking robust immunogenic cell death (ICD) to trigger anti-tumor immune response. Importantly, the released 2DG markedly inhibits lactate generation through glycolysis obstruction. Decreased lactate efflux remodels the immunosuppressive TME by suppressing M2 macrophage proliferation and downregulating regulatory T cell levels. This work provides a new paradigm for the integration of NIR-II phototheranostics and lactate metabolism regulation into a single nanoplatform for amplified anti-tumor immunotherapy combined with ICB therapy.

Degradable tumor-specific H2S nanogenerators for disrupting tumor metabolic symbiosis and activating anti-tumor immune responses

The design of highly efficacious nanotherapeutic agents that target tumors and degrade in specific response is of great relevance and developmental promise. We have designed a tumor-specific decomposable H2S nanogenerator for the purpose of safely and effectively disrupting tumor metabolic symbiosis and activating anti-tumor immune responses. Dendritic mesoporous organosilica doped with Mn2+ (DMOM) was used as a H2S donor that could be specifically degraded in response to glutathione (GSH), and then α-Cyano-4-hydroxycinnamic acid (CHC, a monocarboxylate transporter protein inhibitor) was loaded on the pores and surface of the organosilica through a condensation reaction, and further modified with hyaluronic acid (HA). The H2S nanogenerator could target the tumor site and undergo continuous self-degradation, releasing doped Mn2+ and loaded CHC while depleting GSH and generating large amounts of H2S, which could ultimately destroy lactate metabolic symbiosis, induce multiple acidosis in tumor cells, reduce intracellular adenosine triphosphate (ATP) and enhance chemodynamic therapy. More importantly, both the H2S produced and the inhibition of lactate efflux could have an immunomodulatory effect and exert a positive influence on the activation of the immune system. Therefore, the tumor-specific degradable H2S nanogenerator with diverse therapeutic functions introduced in this work is expected to provide a new idea and a new paradigm for efficient anti-tumor therapy.

Cu+/Ca2+ Dual‐Overload Strategy Assisted by Metabolic‐Symbiotic‐Destruction for Tumor Apoptosis and Tumor Immune Activation

Abstract Ion interference including copper (Cu+)/calcium (Ca2+) overload activate cell‐specific death channels, damage mitochondria and disrupt cellular homeostasis, showing great potential in anti‐tumor therapy. However, the complex metabolic environment and the powerful self‐protection of tumors cause clinical failure of ion interference. Thus, metabolic disruption is expected an innovative strategy for the enhancement of ion interference. Herein, CuS‐α‐CHCA&penthiopyrad@CaCO3‐RGD nanoparticles (CCPCR NPs) are prepared to provide a Cu+/Ca2+ dual‐overload anti‐tumor therapy assisted by metabolic‐symbiosis‐destruction strategy, realizing the collapse of tumor self‐protection. Specifically, precise CuS and CaCO3 delivery triggered irreversible Cu+/Ca2+ dual‐overload and reactive oxygen species (ROS) attack toward 4T1 cells. Meanwhile, α‐CHCA and penthiopyrad disturbed the metabolic symbiotic environment by disrupting the TCA cycle and preventing lactate efflux to aggravate intracellular acidosis and promote Fenton‐like reaction of Cu+, enhancing the sensitivity of tumor cells to copper death and Ca2+ overload. Further, aided by the metabolism of symbiosis, the destroyed tumor cells further activate the polarization of M1 macrophages and the maturation and antigen cross‐presentation of dendritic cells (DCs), which further eliminate tumor cells. In summary, an amplified anti‐tumor dual‐ion interference strategy assisted by metabolic symbiotic destruction is established, which is of great significance in improving the clinical effect of ion therapy for tumors.

MIF/NR3C2 axis regulates glucose metabolism reprogramming in pancreatic cancer through MAPK-ERK and AP-1 pathways.

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth and progression in PDAC. MIF positively correlates with the HK1 (hexokinase 1), HK2 (hexokinase 2) and LDHA (lactate dehydrogenase) expression and increased pyruvate and lactate production in PDAC patients. Additionally, MIF augments glucose uptake and lactate efflux by upregulating HK1, HK2 and LDHA expression in pancreatic cancer cells in vitro and in mouse models of PDAC. Conversely, a reduction in HK1, HK2 and LDHA expression is observed in tumors with high NR3C2 expression in PDAC patients. NR3C2 suppresses HK1, HK2 and LDHA expression, thereby inhibiting glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves the activation of the mitogen-activated protein kinase-ERK signaling pathway, whereas NR3C2 interacts with the activator protein 1 to regulate glycolysis. Our findings reveal an interactive role of the MIF/NR3C2 axis in regulating glucose metabolism supporting tumor growth and progression and may be a potential target for designing novel approaches for improving disease outcome.

Abstract 4426: Targeting MCT1 and PFKFB3 provokes synthetic lethality in small cell lung cancer

Abstract Small cell lung cancer (SCLC) is the third most common lung cancer and is extremely aggressive and highly metastatic. SCLC responds to radiation and standard platinum-based chemotherapy, yet this is invariably followed by relapse and the rapid emergence of lethal chemoresistant disease. Hence, SCLC has been declared a recalcitrant malignancy by NCI, and there is an urgent need to identify new and actionable therapeutic vulnerabilities. Unbiased metabolomic and shotgun and activity-based proteomic analyses of NSCLC and SCLC patient derived tumor tissues, PDX and a panel of cell lines revealed marked upregulation of glycolytic and nucleotide metabolic pathways in SCLC. Further, unbiased screens with metabolic inhibitors revealed selective sensitivity of SCLC cells to the MCT1 lactate transporter inhibitor SR13800 and to the PFKFB3 inhibitor PFK15, and that combined treatment provokes rapid apoptosis. Metabolic, flux and molecular analyses revealed that MCT1 inhibition (MCT1i) or loss in SCLC cells impairs glycolysis and triggers rapid increases in intracellular lactate that then diminish, and this is driven by the induction of lactate dehydrogenase-B (LDH-B) that oxidizes lactate into pyruvate. This is accompanied by a marked shift in the NAD+ to NADH ratio towards NADH, and increased pyruvate dehydrogenase (PDH) activity and OXPHOS. Further, MCT1 inhibition provoked increases in the Aspartate-Malate and DHAP-SnG3P shuttles, which restored the NAD+/NADH balance in the cytosol. In contrast, treatment of SCLC cells with PFKFB3 inhibitors (PFKFB3i) leads to inhibition of PDH activity, a collapse in OXPHOS and increases in lactate efflux that are due to flux of glucose through pentose phosphate pathway and re-entry into glycolysis via 3-phosphoglygerate (3-PGA). Combined MCT1/PFKFB3 inhibition amplifies metabolic alterations provoked by both MCT1i and PFKFB3i, triggering a collapse in both glycolysis and OXPHOS. Similarly, inhibition or silencing of enzymes that drive the Aspartate-Malate and DHAP-SnG3P shuttles, or inhibition of the mitochondrial pyruvate transporter, provoked metabolic collapse and cell death following inhibition or loss of MCT1. Finally, SCLC xenografts and primary SCLC CDX treated with a combination of SR13800 and PFK15 showed improved survival compared to vehicle or monotherapy treatments. Thus, co-targeting adaptive metabolic circuits provoked by inhibition of MCT1 and PFKFB3 provokes synthetic lethality in SCLC, supporting the notion that inhibition of these metabolic chokepoints will be an effective strategy for treatment of this lethal malignancy. Citation Format: Antony Herold Prabhu, Kristen Scott, Paul Stewart, Daniel Grass, Mario Fernandez, Dalia Ercan, John Koomen, Thomas Bannister, Charles Rudin, Gina DeNicola, Eric Haura, John Cleveland. Targeting MCT1 and PFKFB3 provokes synthetic lethality in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4426.

MCT4-dependent lactate transport: a novel mechanism for cardiac energy metabolism injury and inflammation in type 2 diabetes mellitus

Diabetic cardiomyopathy (DCM) is a major contributor to mortality in diabetic patients, characterized by a multifaceted pathogenesis and limited therapeutic options. While lactate, a byproduct of glycolysis, is known to be significantly elevated in type 2 diabetes, its specific role in DCM remains uncertain. This study reveals an abnormal upregulation of monocarboxylate transporter 4 (MCT4) on the plasma membrane of cardiomyocytes in type 2 diabetes, leading to excessive lactate efflux from these cells. The disruption in lactate transport homeostasis perturbs the intracellular lactate-pyruvate balance in cardiomyocytes, resulting in oxidative stress and inflammatory responses that exacerbate myocardial damage. Additionally, our findings suggest increased lactate efflux augments histone H4K12 lactylation in macrophages, facilitating inflammatory infiltration within the microenvironment. In vivo experiments have demonstrated that inhibiting MCT4 effectively alleviates myocardial oxidative stress and pathological damage, reduces inflammatory macrophage infiltration, and enhances cardiac function in type 2 diabetic mice. Furthermore, a clinical prediction model has been established, demonstrating a notable association between peripheral blood lactate levels and diastolic dysfunction in individuals with type 2 diabetes. This underscores the potential of lactate as a prognostic biomarker for DCM. Ultimately, our findings highlight the pivotal involvement of MCT4 in the dysregulation of cardiac energy metabolism and macrophage-mediated inflammation in type 2 diabetes. These insights offer novel perspectives on the pathogenesis of DCM and pave the way for the development of targeted therapeutic strategies against this debilitating condition.

MCT4-driven CAF-mediated metabolic reprogramming in breast cancer microenvironment is a vulnerability targetable by miR-425-5p

Multiple oncogenic alterations contribute to breast cancer development. Metabolic reprogramming, deeply contributing to tumor microenvironment (TME) education, is now widely recognized as a hallmark of cancer. The reverse Warburg effect induces cancer-associated fibroblasts (CAFs) to produce and secrete L-lactate, enhancing malignant characteristics such as neoangiogenesis, metastatic dissemination, and treatment resistance. Monocarboxylate transporter (MCT) 4 is involved in lactate efflux from CAFs into stromal and epithelial cells. Here, we first assess the expression of miR-425-5p and its target MCT4 in breast cancer CAFs and normal fibroblasts. We analyzed the metabolic changes induced by miR-425-5p in CAFs and its role in the education of breast cancer epithelial cells. We show that miR-425-5p-induced MCT4 knockdown decreased lactate extrusion from CAFs and its availability in the TME. miR-425-5p overexpression induced profound metabolic transformation in CAFs, ultimately influencing breast cancer metabolism. Furthermore, miR-425-5p impaired the capacity of CAFs to sustain vessel formation and breast cancer cell migration, viability, and proliferation. These findings emphasize the key role of miR-425-5p in breast cancer metabolism and aggressiveness, and its possible importance for breast cancer therapy and monitoring.

New mechanisms: From lactate to lactylation to rescue heart failure.

Lactylation of α-myosin heavy chain (α-MHC) has recently been reported to preserve sarcomeric structure and function and attenuate the development of heart failure. Specifically, lactylation enhanced the interaction of α-MHC with the sarcomeric protein Titin, thereby maintaining normal sarcomeric structure and myocardial contractile function. Furthermore, the administration of lactate or inhibition of lactate efflux potentially treats heart failure by restoring lactylation of α-MHC and the interaction of α-MHC with Titin. This finding highlights the significant role of α-MHC lactylation in myocardial diseases and presents a new therapeutic target for the treatment of heart failure.

Bicarbonate-Dependent Detoxification by Mitigating Ammonium-Induced Hypoxic Stress in Triticum aestivum Root.

Ammonium (NH4+) toxicity is ubiquitous in plants. To investigate the underlying mechanisms of this toxicity and bicarbonate (HCO3-)-dependent alleviation, wheat plants were hydroponically cultivated in half-strength Hoagland nutrient solution containing 7.5 mM NO3- (CK), 7.5 mM NH4+ (SA), or 7.5 mM NH4+ + 3 mM HCO3- (AC). Transcriptomic analysis revealed that compared to CK, SA treatment at 48 h significantly upregulated the expression of genes encoding fermentation enzymes (pyruvate decarboxylase (PDC), alcohol dehydrogenase (ADH), and lactate dehydrogenase (LDH)) and oxygen consumption enzymes (respiratory burst oxidase homologs, dioxygenases, and alternative oxidases), downregulated the expression of genes encoding oxygen transporters (PIP-type aquaporins, non-symbiotic hemoglobins), and those involved in energy metabolism, including tricarboxylic acid (TCA) cycle enzymes and ATP synthases, but upregulated the glycolytic enzymes in the roots and downregulated the expression of genes involved in the cell cycle and elongation. The physiological assay showed that SA treatment significantly increased PDC, ADH, and LDH activity by 36.69%, 43.66%, and 61.60%, respectively; root ethanol concentration by 62.95%; and lactate efflux by 23.20%, and significantly decreased the concentrations of pyruvate and most TCA cycle intermediates, the complex V activity, ATP content, and ATP/ADP ratio. As a consequence, SA significantly inhibited root growth. AC treatment reversed the changes caused by SA and alleviated the inhibition of root growth. In conclusion, NH4+ treatment alone may cause hypoxic stress in the roots, inhibit energy generation, suppress cell division and elongation, and ultimately inhibit root growth, and adding HCO3- remarkably alleviates the NH4+-induced inhibitory effects on root growth largely by attenuating the hypoxic stress.

Abstract A039: Metabolic evolution in breast cancer predicts organ-specific metastasis

Abstract The metastatic cascade is a critical component of cancer evolution. Understanding the rewired metabolism in organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of metastatic disease. Here, we used a systems biology approach to assess the evolution of metabolic fluxes from parental breast cancer cells to their brain- and lung-homing metastatic derivatives. We found that divergent lineages had distinct, heritable metabolic fluxes. Lung-homing cells maintained adaptations for high glycolytic flux despite low levels of glycolytic intermediates, constitutively activating a pathway sink into lactate. This exacerbated Warburg effect –– stronger than the Warburg effect in the primary tumor –– was associated with a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) expression, a signature which correlated with lung metastasis in patients with breast cancer. While feature classification models trained on clinical characteristics alone were unable to predict tropism, the LDH/PDH ratio was a significant predictor of a patient's future metastasis to the lung but not to other organs, independent of other transcriptomic signatures. Lung- and brain-homing lineages had differential selection patterns in acidic metabolic microenvironments. High lactate efflux was also a trait in lung-homing metastatic pancreatic cancer cells, suggesting that lactate production may be a convergent phenotype in lung metastasis. Together, these analyses highlight the essential role that metabolic evolution plays in organ-specific cancer metastasis and identify a putative biomarker for predicting lung metastasis in breast cancer patients. Citation Format: Deepti Mathur, Chen Liao, Wendy Lin, Alessandro La Ferlita, Salvatore Alaimo, Samuel Taylor, Yi Zhong, Christine Iacobuzio-Donahue, Alfredo Ferro, Joao Xavier. Metabolic evolution in breast cancer predicts organ-specific metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A039.

Co-Delivery of Metabolic Modulators Leads to Simultaneous Lactate Metabolism Inhibition And Intracellular Acidification for Synergistic Cancer Therapy.

Simultaneous lactate metabolism inhibition and intracellular acidification (LIIA) is a promising approach for inducing tumor regression by depleting ATP. However, given the limited efficacy of individual metabolic modulators, a combination of various modulators is required for highly efficient LIIA. Herein, a co-delivery system that combines lactate transporter inhibitor, glucose oxidase, and O2 -evolving nanoparticles is proposed. As a vehicle, a facile room-temperature synthetic method for large-pore mesoporous silica nanoparticles (L-MSNs) is developed. O2 -evolving nanoparticles are then conjugated onto L-MSNs, followed by immobilizing the lactate transporter inhibitor and glucose oxidase inside the pores of L-MSNs. To load the lactate transporter inhibitor, which is too small to be directly loaded into the large pores, it is encapsulated in albumin by controlling the albumin conformation before being loaded into L-MSNs. Notably, inhibiting lactate efflux shifts the glucose consumption mechanism from lactate metabolism to glucose oxidase reaction, which eliminates glucose and produces acid. This leads to synergistic LIIA and subsequent ATP depletion in cancer cells. Consequently, L-MSN-based co-delivery of modulators for LIIA shows high anticancer efficacy in several mouse tumor models without toxicity in normal tissues. This study provides new insights into co-delivery of small-molecule drugs, proteins, and nanoparticles for synergistic metabolic modulation in tumors. This article is protected by copyright. All rights reserved.

MCT4 blockade increases the efficacy of immune checkpoint blockade

Background & AimsIntratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, turned out to be...

Acidity-Responsive Nanoreactors Destructed "Warburg Effect" for Toxic-Acidosis and Starvation Synergistic Therapy.

"Warburg Effect" shows that most tumor cells rely on aerobic glycolysis for energy supply, leading to malignant energy deprivation and an "internal alkaline external acid" tumor microenvironment. Destructing the "Warburg Effect" is an effective approach to inhibit tumor progression. Herein, an acidity-responsive nanoreactor (Au@CaP-Flu@HA) is fabricated for toxic acidosis and starvation synergistic therapy. In the nanoreactor, the fluvastatin (Flu) could reduce lactate efflux by inhibiting the lactate-proton transporter (monocarboxylate transporters, MCT4), resulting in intracellular lactate accumulation. Meanwhile, the glucose oxidase-mimic Au-nanocomposite consumes glucose to induce cell starvation accompanied by gluconic acid production, coupling with lactate to exacerbate toxic acidosis. Also, the up-regulated autophagic energy supply of tumor cells under energy deprivation and hypoxia aggravation is blocked by autophagy inhibitor CaP. Cellular dysfunction under pHi acidification and impaired Adenosine Triphosphate (ATP) synthesis under starvation synergistically promote tumor cell apoptosis. Both in vitro and in vivo studies demonstrate that this combinational approach of toxic-acidosis/starvation therapy could effectively destruct the "Warburg Effect" to inhibit tumor growth and anti-metastatic effects.

α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure

The sarcomeric interaction of α-myosin heavy chain (α-MHC) with Titin is vital for cardiac structure and contraction. However, the mechanism regulating this interaction in normal and failing hearts remains unknown. Lactate is a crucial energy substrate of the heart. Here, we identify that α-MHC undergoes lactylation on lysine 1897 to regulate the interaction of α-MHC with Titin. We observed a reduction of α-MHC K1897 lactylation in mice and patients with heart failure. Loss of K1897 lactylation in α-MHC K1897R knock-in mice reduces α-MHC–Titin interaction and leads to impaired cardiac structure and function. Furthermore, we identified that p300 and Sirtuin 1 act as the acyltransferase and delactylase of α-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation reduces α-MHC lactylation, impairs α-MHC–Titin interaction and worsens heart failure. By contrast, upregulation of the lactate concentration by administering sodium lactate or inhibiting the pivotal lactate transporter in cardiomyocytes can promote α-MHC K1897 lactylation and α-MHC–Titin interaction, thereby alleviating heart failure. In conclusion, α-MHC lactylation is dynamically regulated and an important determinant of overall cardiac structure and function. Excessive lactate efflux and consumption by cardiomyocytes may decrease the intracellular lactate level, which is the main cause of reduced α-MHC K1897 lactylation during myocardial injury. Our study reveals that cardiac metabolism directly modulates the sarcomeric structure and function through lactate-dependent modification of α-MHC.

An enzyme-instructed self-assembly system induces tumor acidosis via sequential-dual effect for cancer selective therapy.

The acidosis anti-tumor therapy, based on the altered energy metabolism pathway of tumor cells, has been proposed as an attractive method for cancer selective treatment. However, the strategy of inducing tumor acidosis by using a single drug to simultaneously inhibit both lactate efflux and consumption has not been reported yet. Herein, an in situ enzyme-instructed self-assembly (EISA) system was rationally fabricated to induce tumor acidosis apoptosis for cancer selective therapy. Depending on the sequential effect of the in situ EISA system, the targeted drug was successively distributed on the membrane and intracellular, inhibiting MCT4 mediated lactate efflux and mitochondrial tricarboxylic acid (TCA) cycle mediated lactate consumption, respectively. Through the dual obstruction of lactate metabolism to trigger tumor acidosis, the in situ EISA nanomedicine showed selective growth and migration inhibition against cancer cells. In addition, the nanomedicine also displayed a radio-sensitization effect in vitro due to causing the mitochondrial dysfunction, and exhibited a prominent synergistic chemo-radiotherapy anti-tumor performance in vivo. Accordingly, this work demonstrated that the in situ EISA system could endow the LND with sequential-dual effects to induce tumor acidosis, which may provide an enlightening strategy for anticancer drug delivery and cancer selective therapy. STATEMENT OF SIGNIFICANCE: With the help of the sequential effect of in situ EISA , the serial attack of LND against different targets was effectively realized to induce tumor acidosis and combined chemo-radiotherapy, implying the importance of the relationship between structure and function, which could offer a distinctive inspiration for future drug delivery system design and anti-tumor application.

Lactate Efflux Inhibition by Syrosingopine/LOD Co-Loaded Nanozyme for Synergetic Self-Replenishing Catalytic Cancer Therapy and Immune Microenvironment Remodeling.

An effective systemic mechanism regulates tumor development and progression; thus, a rational design in a one-stone-two-birds strategy is meant for cancer treatment. Herein, a hollow Fe3 O4 catalytic nanozyme carrier co-loading lactate oxidase (LOD) and a clinically-used hypotensor syrosingopine (Syr) are developed and delivered for synergetic cancer treatment by augmented self-replenishing nanocatalytic reaction, integrated starvation therapy, and reactivating anti-tumor immune microenvironment. The synergetic bio-effects of this nanoplatform stemmed from the effective inhibition of lactate efflux through blocking the monocarboxylate transporters MCT1/MCT4 functions by the loaded Syr as a trigger. Sustainable production of hydrogen peroxide by catalyzation of the increasingly residual intracellular lactic acid by the co-delivered LOD and intracellular acidification enabled the augmented self-replenishing nanocatalytic reaction. Large amounts of produced reactive oxygen species (ROS) damaged mitochondria to inhibit oxidative phosphorylation as the substituted energy supply upon the hampered glycolysis pathway of tumor cells. Meanwhile, remodeling anti-tumor immune microenvironment is implemented by pH gradient reversal, promoting the release of proinflammatory cytokines, restored effector T and NK cells, increased M1-polarize tumor-associated macrophages, and restriction of regulatory T cells. Thus, the biocompatible nanozyme platform achieved the synergy of chemodynamic/immuno/starvation therapies. This proof-of-concept study represents a promising candidate nanoplatform for synergetic cancer treatment.