Hot Ones Research Articles

Multifunctional Theranostic 2D Vanadium Carbidel for Enhanced Cancer Immunotherapy

AbstractThe application of 2D MXene materials in the biomedical field has been widely explored. Apart from excellent photothermal properties, their role in modulating various immune cells and overcoming immune‐suppressive tumor microenvironments is waiting to be discovered. In this work, a novel multifunctional 2D vanadium carbide is constructed that degrades in situ in the tumor microenvironment. Various characterizations and first‐principles calculations indicated that V4C3 nanosheets exhibit excellent light absorption and photothermal conversion capabilities in the NIR‐II biological window. The photothermal and X‐ray absorption properties of V4C3 nanosheets enabled dual‐modal photoacoustic imaging/computerized tomography (PA/CT) imaging functionality. The V4C3 nanosheets in the tumor microenvironment decomposed under the effect of H2O2 and GSH, triggering a Fenton‐like reaction. The photothermal ablation and reactive oxygen species (ROS) generation capabilities enabled V4C3 nanosheets to convert cold tumors into hot ones (macrophage: M2→M1) and induce reactions like immunogenic cell death (ICD). Dendritic cell (DC) cells matured under the ICD stimulation, which promoted T cell activation, reduced Treg cells and thus effectively enhanced tumor immunotherapy. The multiple properties including imaging, photothermal, enzyme‐driven, and immune functions enable V4C3 nanosheets to ablate tumors effectively. This study provides an example for the research of the multifunctional exploration and application of MXene in biomedicine filed.

HDAC inhibitor regulates the tumor immune microenvironment via pyroptosis in triple negative breast cancer.

Pyroptosis, an inflammatory form of cell death, promotes the release of immunogenic substances and stimulates immune cell recruitment, a process, which could turn cold tumors into hot ones. Thus, instigating pyroptosis in triple-negative breast cancer (TNBC) serves as a viable method for restoring antitumor immunity. We analyzed the effects of Histone Deacetylase Inhibitors (HDACi) on TNBC cells using the Cell Counting Kit-8 and colony formation assay. Apoptosis and lactate dehydrogenase (LDH) release assays were utilized to determine the form of cell death. The pyroptotic executor was validated by quantitative real-time polymerase chain reaction and western blot. Transcriptome was analyzed to investigate pyroptosis-inducing mechanisms. A subcutaneously transplanted tumor model was generated in BALB/c mice to evaluate infiltration of immune cells. HDACi significantly diminished cell proliferation, and pyroptotic "balloon"-like cells became apparent. HDACi led to an intra and extracellular material exchange, signified by the release of LDH and the uptake of propidium iodide. Among the gasdermin family, TNBC cells expressed maximum quantities of GSDME, and expression of GSDMA, GSDMB, and GSDME were augmented post HDACi treatment. Pyroptosis was instigated via the activation of the caspase 3-GSDME pathway with the potential mechanisms being cell cycle arrest and altered intracellular REDOX balance due to aberrant glutathione metabolism. In vivo experiments demonstrated that HDACi can activate pyroptosis, limit tumor growth, and escalate CD8+ lymphocyte and CD11b+ cell infiltration along with an increased presence of granzyme B in tumors. HDACi can instigate pyroptosis in TNBC, promoting infiltration of immune cells and consequently intensifying the efficacy of anticancer immunity.

Synergistic effects of Smac mimetic APG-1387 with anti-PD-1 antibody are attributed to increased CD3 + NK1.1 + cell recruitment secondary to induction of cytokines from tumor cells

BackgroundImmune checkpoint inhibitors are approved for the treatment of various tumors, but the response rate is not satisfactory in certain malignancies. Inhibitor of apoptosis proteins (IAP) ubiquitin-E3 ligase activity is involved in the regulation of immune responses. APG-1387 is a novel second mitochondria-derived activator of caspase (Smac) mimetic IAP inhibitor. The aim of this study was to explore the synergistic effect of APG-1387 when combined with anti-PD-1 antibody in a preclinical setting.MethodsWe utilized syngeneic mouse models of ovarian cancer (ID8), colon cancer (MC38), malignant melanoma (B16), and liver cancer (Hepa1-6) to assess the combination effect of APG-1387 and anti-PD-1 antibody, including immune-related factors, tumor growth, and survival. MSD V-PLEX validated assays were used to measure in vitro and in vivo cytokine release.ResultsIn ID8 ovarian cancer and MC38 colon cancer models, APG-1387 and anti-PD1 antibody had synergistic antitumor effects. In the MC38 model, the combination of APG-1387 and anti-PD-1 antibody significantly inhibited tumor growth (P < 0.0001) and increased the survival rate of tumor-bearing animals (P < 0.001). Moreover, we found that APG-1387 upregulated tumor-infiltrating CD3 + NK1.1 + cells by nearly 2-fold, by promoting tumor cell secretion of IL-12. Blocking IL-12 secretion abrogated the synergistic effects of APG-1387 and anti-PD-1 antibody in both MC38 and ID8 models.ConclusionsAPG-1387 has the potential to turn “cold tumors” into hot ones by recruiting more CD3 + NK1.1 + cells into certain tumors. Based on these and other data, the safety and therapeutic effect of this combination will be investigated in a phase 1/2 trial in patients with advanced solid tumors or hematologic malignancies (NCT03386526).Graphic abstract

Mitochondria-Targeted Nanoadjuvants Induced Multi-Functional Immune-Microenvironment Remodeling to Sensitize Tumor Radio-Immunotherapy.

It is newly revealed that collagen works as a physical barrier to tumor immune infiltration, oxygen perfusion, and immune depressor in solid tumors. Meanwhile, after radiotherapy (RT), the programmed death ligand-1 (PD-L1) overexpression and transforming growth factor-β (TGF-β) excessive secretion would accelerate DNA damage repair and trigger T cell exclusion to limit RT efficacy. However, existing drugs or nanoparticles can hardly address these obstacles of highly effective RT simultaneously, effectively, and easily. In this study, it is revealed that inducing mitochondria dysfunction by using oxidative phosphorylation inhibitors like Lonidamine (LND) can serve as a highly effective multi-immune pathway regulation strategy through PD-L1, collagen, and TGF-β co-depression. Then, IR-LND is prepared by combining the mitochondria-targeted molecule IR-68 with LND, which then is loaded with liposomes (Lip) to create IR-LND@Lip nanoadjuvants. By doing this, IR-LND@Lip more effectively sensitizes RT by generating more DNA damage and transforming cold tumors into hot ones through immune activation by PD-L1, collagen, and TGF-β co-inhibition. In conclusion, the combined treatment of RT and IR-LND@Lip ultimately almost completely suppressed the growth of bladder tumors and breast tumors.

Focused Ultrasound as Targeted Therapy for Colorectal Cancer: A Comprehensive Review

Traditional cancer treatments have not significantly improved the survival rates for individuals with colorectal cancer. As a result, there is a dire need to explore novel treatment modalities that can target cancer-specific niches, transform cold colorectal tumors into hot ones, and disrupt the tumor niche. Therapeutic focused ultrasound, recognized for its capacity to induce thermal and mechanical impacts on tissue, can potentially eliminate cancer cells and elicit the body’s anticancer reaction by disrupting the tumor microenvironment. This article provides an overview of recent developments in employing therapeutic focused ultrasound (TFUS) to enhance the body’s natural defenses against colorectal cancers. It also discusses studies examining the utility of TFUS in treating colorectal cancer patients and recent research indicating its potential to stimulate the body’s anticancer response in various in vitro and in vivo colorectal cancer models. Furthermore, it explores the therapeutic effects of TFUS on the immune system in colorectal cancers. This article also highlights the safety and effectiveness of TFUS in managing colorectal cancer, providing relief from pain, and potentially improving survival rates. Given the indications that TFUS may bolster the body’s immune response and augment the impacts of TFUS therapy in clinical and preclinical colorectal cancer models, it has the potential to emerge as a pivotal tool in clinical settings.

Immunologic tumor microenvironment modulators for turning cold tumors hot.

Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment (TME). Hot tumors, characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors (ICIs), stand in stark contrast to cold tumors, which lack immune infiltration and remain resistant to therapy. To overcome immune evasion mechanisms employed by tumor cells, novel immunologic modulators have emerged, particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1). These agents disrupt inhibitory signals and reactivate the immune system, transforming cold tumors into hot ones and promoting effective antitumor responses. However, challenges persist, including primary resistance to immunotherapy, autoimmune side effects, and tumor response heterogeneity. Addressing these challenges requires innovative strategies, deeper mechanistic insights, and a combination of immune interventions to enhance the effectiveness of immunotherapies. In the landscape of cancer medicine, where immune cold tumors represent a formidable hurdle, understanding the TME and harnessing its potential to reprogram the immune response is paramount. This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies, offering hope for patients with immune-resistant tumors.

Trends In Extreme Weather Events With Socio-Economic Damage Over The Period 1991-2019 In Russia And Its Regions

Increased number of extreme weather events is one of the most serious hazards of climate change over the territory of Russia. However, there is a lack of comprehensive analysis of the number of extreme weather events that caused social and economic damage in the country and its regions. This paper analyzes changes in the total number of events with damage (meteorological for the period 1991-2019 and agrometeorological – for 2004-2019), disaggregated by their types and by regions. The Mann-Kendall test is applied to detect statistical significance (0.05 level of significance, normal distribution). The results show an increase in the number of meteorological extreme events with damage for 1990-2019 in Russia from 130 to 257 events per year on average for the 1990s and 2010s, respectively, while the proportion of events with damage in relation to the total number of extreme events decreased over this period. We found statistically significant trends only for a few types of extreme events: hot and cold temperature, strong wind, heavy rain and droughts (increase by 0.9, 9.4, 11.4, 25.9 and 13.3 events/10 years, respectively). Number of heavy rain precipitation events is the only unidirectional stable growth trend. Unusual increasing trend in cold extreme events with damage in Russia can be attributed to the greater damage to the economy and population from cold extremes than hot ones. The regional distribution of trends across the territory of the Russian Federation is heterogeneous. However, significant changes in the number of extreme events of strong winds, heavy rains and soil drought by regions are statistically positive and observed mostly in some southern and central regions of European part and the Western Siberia. The development of adaptation plans to the negative effects of climate change is a first priority for these regions. A system for monitoring economic and non-economic damage from extreme events must be developed in Russia.

Revisiting Temozolomide's role in solid tumors: Old is gold?

Temozolomide is an imidazotetrazine with a long history in oncology especially for the high grade malignant glioma and metastatic melanoma. However, last year's new indications for its use are added. Its optimum pharmacodynamic profile, its ability to penetrate the blood-brain barrier, the existence of methylation of MGMT in solid tumors which enhances its efficacy, the identification of new agents that can overcome temozolomide's resistance, the promising role of temozolomide in turning immune cold tumors to hot ones, are leading to expand its use in other solid tumors, giving oncologists an additional tool for the treatment of advanced and aggressive neoplasms.

Fabrication of An Immunostimulatory Supramolecular Nanomedicine for Potent Cancer Chemoimmunotherapy.

Chemoimmunotherapy can boost strong antitumor immune responses by triggering immunogenic cell death (ICD), which highlights a promising prospect in clinical applications. However, current chemoimmunotherapy shows limited efficacy due to the low delivery efficiency and insufficient immunogenicity of available chemotherapeutic drugs. A supramolecular polymeric nanomedicine (Pt-Tu@NP) is herein reported using cucurbit[7]uril-based host-guest recognition and noncovalent self-assembly. Pt-Tu@NPs have excellent biodistribution and strongly evoke the endoplasmic reticulum stress-mediated ICD of tumor cells, triggering potent antitumor immune responses by promoting dendritic cell (DC) maturation and cytotoxic T cell infiltration. The coordinated butyrate promotes a positive feedback regulation between DCs and CD8+ T cells. Pt-Tu@NPs stimulate immune cold tumors into hot ones, working in synergy with an immune checkpoint blockade to effectively suppress tumor growth and metastasis, which suggests a promising approach for cancer chemoimmunotherapy.

Promoción de funciones ejecutivas en adolescentes con desarrollo típico: revisión sistemática

During adolescence, hot and cold executive functions are still developing, making it essential to assess and intervene if changes occur. The present study aims to identify, through a systematic review, which interventions in executive functions have been studied in typical adolescents, including hot and cold executive functions, seeking to determine the effects of these interventions in this segment. The search was conducted according to the PRISMA method in the PubMed database. Of the 315 articles initially located, five remained after applying exclusion criteria and analyzing by judges. The selected articles revealed a more significant effect of interventions on cold executive functions than hot ones, which may corroborate previous data suggesting that hot executive functions take longer to be stimulated than cold ones. Only one of the five articles jointly stimulated cold and hot executive functions, which reveals the need for more research in the area. The small number of articles selected, despite limiting the conclusions, reinforces the need to conduct more research on intervention in hot and cold executive functions in typically developing adolescents.

MRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy

Synergistically improving T-cell responsiveness is promising for favorable therapeutic outcomes in immunologically cold tumors, yet current treatments often fail to induce a cascade of cancer-immunity cycle for effective antitumor immunity. Gasdermin-mediated pyroptosis is a newly discovered mechanism in cancer immunotherapy; however, cleavage in the N terminus is required to activate pyroptosis. Here, we report a single-agent mRNA nanomedicine-based strategy that utilizes mRNA lipid nanoparticles (LNPs) encoding only the N-terminus of gasdermin to trigger pyroptosis, eliciting robust antitumor immunity. In multiple female mouse models, we show that pyroptosis-triggering mRNA/LNPs turn cold tumors into hot ones and create a positive feedback loop to promote antitumor immunity. Additionally, mRNA/LNP-induced pyroptosis sensitizes tumors to anti-PD-1 immunotherapy, facilitating tumor growth inhibition. Antitumor activity extends beyond the treated lesions and suppresses the growth of distant tumors. We implement a strategy for inducing potent antitumor immunity, enhancing immunotherapy responses in immunologically cold tumors.

Stable food grade wax/attapulgite superhydrophobic coatings for anti-adhesion of liquid foods

Adhesion of liquid foods on their packaging materials has caused significant food wastes and environment pollution, which has attracted great attention. Food grade superhydrophobic coatings are very promising to solve the issue but suffer from low mechanical stability and complex preparation methods. Herein, a food grade superhydrophobic coating for anti-adhesion of liquid foods was prepared by combining edible paraffin wax, polydimethylsiloxane-modified attapulgite natural nanorods and a food grade silicone adhesive. The concentration of polydimethylsiloxane-modified attapulgite, ultrasonication time and the volume ratio of the paraffin wax/attapulgite suspension to the silicone adhesive solution have great influences on wettability and morphology of the coatings. The coatings exhibit good static and dynamic superhydrophobicity due to their hierarchical micro-/nanostructure and low surface energy of the polydimethylsiloxane-modified attapulgite and paraffin wax. Moreover, the coatings exhibit good mechanical and chemical stability. The coatings are also highly repellent towards various liquid foods including the hot ones. Furthermore, the coatings are applicable onto various frequently used flexible and hard food packing materials including polypropylene, polyethylene terephthalate, aluminium alloy and paper, etc. Thus, the superhydrophobic coatings have great application potential in the food packing industry for anti-adhesion of liquid foods.

Multifunctional nanodrug performs sonodynamic therapy and inhibits TGF-β to boost immune response against colorectal cancer and liver metastasis.

Liver metastasis is the leading cause of death in colorectal cancer. Immunotherapy using immune checkpoint blockade (ICB) is ineffective due to its immunological cold tumor nature. Herein, we prepared a nanodrug (NCG) encapsulating the transforming growth factor-β receptor inhibitor galunisertib (Gal) and the sonosensitizer chlorin e6 (Ce6), which was aimed to turn this type of cold tumor into a hot one to promote the ICB-based immunotherapy against it. After delivery to the tumor, NCG under ultrasonic irradiation generated reactive oxygen species causing tumor immunogenic cell death and releasing immunostimulatory signals such as calreticulin and HMGB1, which increased tumor immunogenicity and activated the innate T lymphocyte immune response. Moreover, NCG responded to the acidic microenvironment and released Gal, inhibiting phosphorylation and inducing immunosuppressive Smad2/3 signaling. Consequently, the differentiation of MDSCs was inhibited, M1-like polarization of tumor-associated macrophages was induced, and the immunosuppressive barrier of tumor-associated fibroblasts was destroyed to increase the infiltration of effector T cells, which reversed the immunosuppression of the tumor microenvironment and improved the therapeutic efficacy of anti-PD-L1 antibodies. Notably, in the liver metastasis mouse model, combination therapy using NCG (+) and aPD-L1 inhibited the growth of colon cancer liver metastasis, manifesting potential in treating this popular yet intractable malignancy. STATEMENT OF SIGNIFICANCE: Only a limited number of patients with colorectal cancer and liver metastasis can benefit from immune checkpoint blockade therapy, as most of them are microsatellite stable, immunologically cold tumors. Interestingly, there is compelling evidence that sonodynamic therapy (SDT) can convert immunosuppressed cold tumors into hot ones, trigger tumor immunogenic cell death non-invasively, and boost cytotoxic T cells infiltration. However, its therapeutic efficacy is constrained by the abundance of transforming growth factor-β (TGF-β) cytokines in the tumor microenvironment. Here, we reported a TGF-β-targeted inhibitory nanodrug that improved SDT in colon cancer and liver metastasis, reversed the immunosuppressive tumor microenvironment and boosted the immune response to anti-PD-L1 therapy in this cancer. It demonstrated the potential to cure this prevalent but incurable malignancy.

Can the MDCDW condensate withstand the heat of a cold neutron star?

The correct description of strongly interacting matter at low temperatures and moderately high densities—in particular the conditions realized inside neutron stars—is still unknown. We review some recent results on the magnetic dual chiral density wave (MDCDW) phase, a candidate phase of quark matter for this region of the QCD phase diagram. We highlight the effects of magnetic fields and temperature on the condensate, which can be explored using a high-order Ginzburg-Landau (GL) expansion. We also explain how the condensate’s nontrivial topology, which arises due to the asymmetry in the lowest Landau level modes, affects its physical properties. Finally, we comment on the possible relevance of these results to neutron star applications. Over a wide range of densities and magnetic field strengths, MDCDW is preferred over the chirally symmetric ground state at temperatures consistent with typical cold neutron stars, and in some cases, even hot ones.

Structural and Mechanical Properties of Modified Hot and Warm Mix Asphalt Concrete

Statement of the problem. The problem of improving the structural and mechanical properties of hot and warm mix asphalt concrete based on mineral materials, produced by Ltd. «PavlovskNerud», Voronezh region, is considered, using the method of polymer-dispersed reinforcement. The effect of the modifier RTEP-M on the resistance of rutting for hot and warm mix asphalt concrete has been studied. Results. By studying hot and warm mixes asphalt with RTEP-M modifier in the amount of 0.3 and 0.6 % by weight in the mineral part, respectively, and the control composition, a significant improvement in structural and mechanical properties was achieved. It is shown that it is possible to increase the resistance of rutting for hot and warm asphalt concrete prepared on local road construction materials by increasing its viscous-elastic properties by using the method of dispersed reinforcement using the Russian additive RTEP-M. Conclusions. The efficiency of using the method of polymer-dispersed reinforcement to improve the structural and mechanical properties of hot and warm asphalt concrete based on local mineral materials has been proven. It is shown that the addition of the RTEP-M modifier to the mineral part of hot and warm asphalt concrete mix in the amount of 0.3 and 0.6 % by weight, respectively, improves the rutting resistance of the road surface. It has been proved that by applying the method of polymer-dispersed reinforcement, it is possible to optimize the properties of warm asphalt concrete for its use in hot climatic conditions for the introduction of warm technologies instead of hot ones in the construction and repair of road surfaces.

In Situ Vaccination with Mitochondria-Targeting Immunogenic Death Inducer Elicits CD8+ T Cell-Dependent Antitumor Immunity to Boost Tumor Immunotherapy.

In situ vaccination can elicit systemic antitumor immunity to potentiate immune checkpoint blockade (ICB) in poorly immunogenic tumors. Herein, an immunogenic cell death (ICD) inducer for in situ vaccination, which is based on a mitochondria-targeting modification of fenofibric acid (FFa), a lipid-lowering drug with potential inhibitory efficacy of respiratory complex I is developed. Mitochondria-targeting FFa (Mito-FFa) inhibits complex I efficiently and increases mitochondrial ROS (mtROS) generation, which further triggers endoplasmic reticulum (ER) stress with unprecedented calreticulin (CRT) exposure on tumor cellular membranes. Moreover, the generated mtROS also oxidizes mitochondrial DNA (mtDNA) and promotes it leakage into the cytoplasm for cGAS-STING-dependent type I interferon (IFN-I) secretion. The synchronous CRT exposure and IFN-I secretion successively improve the uptake of tumor antigens, maturation of dendritic cells (DCs) and cross-priming of CD8+ T cells. In a poorly immunogenic 4T1 tumor model, a single intratumoral (i.t.) Mito-FFa injection turns immune-cold tumors into hot ones and elicits systemic tumor-specific CD8+ T cells responses against primary and metastatic tumors. Furthermore, the synergistic effect with PD-L1 blockade and good bio-safety of i.t. Mito-FFa administration suggest the great translational potential of Mito-FFa in tumor immunotherapy.

Comparison of Characterization of Cold Brew and Hot Brew Coffee Prepared at Various Roasting Degrees

This investigation is aimed at elucidating the effects of roasting degree and extraction method on coffee beverages prepared with beans from Asia. According to the results with the improvement of the roasting degree, a decrease in titratable acidity, total phenolic compounds, the concentrations of chlorogenic acid and trigonelline, and total antioxidant capacity was observed. Cold coffee beverages showed higher total sugar and trigonelline. The volatile components, such as pyridine, furan-2-yl-methyl acetate, 2-furanemethanol, and 5-methylfurfural, were also affected by roasting degree and extraction methods. Cold brew coffee exhibited higher intensities of enzymatic flavor and sweetness. Furthermore, the principal component analysis revealed a distinct difference in coffee characterization in roasting degree in cold coffee brews than in hot ones. The results indicate that roasting degree affects physicochemical and sensory properties more than extraction temperature. Additionally, there were significant differences in coffee characteristics between cold and hot brew coffee.

Abstract 1857: Nanoliposomes harness tumor immunity in breast cancer models

Abstract The effect on the immune system of nanoparticles is poorly described. The aim of this study was to analyze in immuno-competent BalbC mice bearing or not 4T1 murine breast cancers, the impact on immune system of blank liposomes (i.e., Lipo) or blank immunoliposomes grafted with trastuzumab with a maleimide linker (i.e., ANC). Both nanoparticles were 120 nm of diameter and were pegylated. Mice were administered with saline solution (Control) or treated with either Lipo or ANC with single-dosing (SD) or multiple-dosing (MD). Impact on immunity in blood, spleen and tumors was monitored in a longitudinal fashion in blood for up to 8 weeks, and once per animal in spleen and tumors (i.e., D18 or D23). Immune cells were analyzed by flow cytometry. In tumor-free mice, in blood a transient increase in B-cells between D7 and D15 was found (p= 0,003; &amp;lt; 0,001 and 0,009, t test) for ANC-MD, Lipo-SD and Lipo-MD, respectively. Of note, mice treated with ANC-MD exhibited persistent increase in B-cells up to 8 weeks. Regarding T-cells, a transient increase of CD4+ and CD8+ lymphocytes from D0 to D15 was observed. In spleen, more CD4+ T-cells than CD8+ cells were found, both with Lipo and ANC. Blank Lipo or blank ANC did not impact the tumor growth as compared with Control, and tumor sizes were comparable among all groups. In tumor-bearing mice, in blood little difference between B-cells was observed among the groups. Considering T-cells, a significant diminution in CD4+ cells was observed throughout time in mice treated with either ANC or Lipo (p=0.029, Anova). Conversely, a sharp increase in CD8+ cells as compared with Control group was observed between D18 and D23 for all the treatment arms (p&amp;lt;0.05, Anova). Of note, ANC-MD and Lipo-MD showed significantly higher CD8+ as compared with SD treatments. In spleen, more CD8+ cells than CD4+ cells were found. Still, CD4+ T-cells tended to increase, including in the Control group, between D18 and D23, whereas no such increase was observed for CD8+ cells. In treated animals, a sharp increase in FOXP3 CD4+ Tregs was observed in spleen. In tumors, B-cells increased in Control group but decreased in both Lipo and ANC-treated animals. A marked decrease in CD4+ cells was observed in Control group, whereas little change was observed in treated mice. Conversely, a sharp increase in CD8+ was observed, especially in mice treated with Lipo-MD and ANC-SD. Interestingly, no Tregs were found in treated mice (i.e., either Lipo or ANC) on D23, whereas Tregs were still observed in Control group. As a conclusion, our data suggest that nanoparticles can reshape tumor immunity indeed. Little difference was found between ANC and Lipo, suggesting the immunomodulating features we observed are probably supported by the pegylated liposomes, and not the grafted trastuzumab. Increase in CD8+ cells in blood and tumors, associated with decrease in Tregs in tumors, suggest that liposomal nanoparticles could help turning cold tumors into hot ones. Citation Format: Mathilde Dacos, Guillaume Sicard, Benoit Immordino, Sarah Giacometti, Joseph Ciccolini, Anne Rodallec, Raphaelle Fanciullino. Nanoliposomes harness tumor immunity in breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1857.

Transforming Cold Tumors into Hot Ones with a Metal-Organic Framework-Based Biomimetic Nanosystem for Enhanced Immunotherapy.

Immunotherapy has revolutionized the landscape in clinical tumor therapy, although the response rates in "cold" tumors are relatively low owing to the complex tumor microenvironment (TME). Cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway-inducing agents can reprogram the TME; however, their applications remain underutilized. Herein, we engineered a facile manganese-based metal-organic framework (Mn-MOF) encapsulating polyphyllin I (PPI) and coated it with red blood cell (RBC) membranes (RBC@Mn-MOF/PPI) that enhanced the cGAS/STING-mediated antitumor immunity. RBC@Mn-MOF/PPI was engineered by camouflaging it with a biomimetic RBC membrane for prolonged blood circulation and immune escape, which was also extended with TME-sensitive properties for triggering the release of PPI and Mn2+ to remodel the suppressive TME and augment antitumor immune responses. Furthermore, RBC@Mn-MOF/PPI helped transform cold tumors into "hot" ones by activating immune cells, as evidenced via dendritic cell maturation, cytotoxic T lymphocyte infiltration, and natural killer cell recruitment, thereby targeting primary and abscopal tumors and lung metastatic nodules. Therefore, our engineered nanosystem represents a novel strategy to transform immunologically "cold" tumors into "hot" ones by activating the cGAS/STING pathway, thereby addressing the major challenges associated with immunotherapy.

High-pressure experimental and thermodynamic constraints on the solubility of carbonates in subduction zone fluids

Carbon on the Earth's surface can be carried into the mantle by subducting slabs in the form of carbonates and organics. However, not all the subducting carbon could be recycled into the Earth's deep mantle because parts of them will be released from the subducting slabs by decarbonation processes (e.g., metamorphism and dissolution). In comparison with metamorphic decarbonation, the dissolution of carbonates in subduction zone fluids is more essential, but not well constrained. In this study, we systematically constrained the solubility of different carbonates (e.g., calcite/aragonite, dolomite, and magnesite) under high-pressure and high-temperature conditions relevant to subduction zones by combining experimental and thermodynamic simulations. We simultaneously compared the dissolution processes of calcite/aragonite, dolomite, and magnesite in aqueous fluids under the same P–T conditions using the four-hole gasket technique in diamond anvil cell (DAC) experiments. In situ Raman spectra of fluids in the DAC clearly showed that dolomite had a similar solubility to aragonite, while the solubility of magnesite was much lower than that of aragonite and dolomite under the same P–T conditions. Notably, we also found that the dissolution of dolomite was an incongruent process via the reaction CaMg(CO3)2(solid) in H2O = MgCO3(solid) + Ca2+(aqueous) + CO32−(aqueous). Based on the experimental results, we reasonably suppressed some aqueous species in the DEW model and quantitatively calculated the speciation and solubility of calcite/aragonite, dolomite, and magnesite in aqueous fluids at pressures up to 5 GPa and temperatures up to 800°C. Then, we modeled and compared the decarbonation fluxes between metamorphism and dissolution from typical marine sediment and altered oceanic crust in subduction zones. In the cold or intermediate subducting slabs, decarbonation fluxes by the dissolution of carbonates are about three times larger than that from metamorphism. Considering the total decarbonation fluxes of metamorphism and dissolution, the cold subducting slabs could release a similar magnitude of carbon as the hot ones.