Despite the breakthroughs of transition-metal catalysts in enzyme mimicking, fundamental investigation on the design of efficient nanozymes at the atomic scale is still required for boosting their intrinsic activities to fill in gaps from enzymes to nanozymes. Herein, we developed a universal salt-template strategy for the fabrication of atomically dispersed Fe atoms on ultrathin nitrogen-doped carbon nanosheets characterized by a dramatically high concentration of 13.5 wt %. The proposed Fe-N-C nanozymes with densely isolated FeN 4 sites show high peroxidase-like activities and exhibit a specific activity of 25.33 U/mg, superior to Zn(Co)-N-C nanozymes. Both experiments and theoretical analysis revealed that FeN 4 sites not only lead to the strong adsorption of H 2 O 2 molecules but also weaken the bonding interaction between single Fe atom and two absorbed hydroxyl groups, lowering the energy barrier of the formation of hydroxyl radicals and therefore boosting their peroxidase-like activities. As expected, utilizing the peroxidase-like activity of Fe-N-C nanozymes, good sensitivity and selectivity for the intracellular H 2 O 2 monitoring were realized. It offers a versatile approach for the construction of densely isolated M-N-C single-atom catalysts and achieves better understanding of single sites for the peroxidase-like catalytic mechanisms.

SUMMARY Limiting the metabolic competition in the tumor microenvironment (TME) may increase the effectiveness of immunotherapy. Because of its critical role in glucose metabolism of activated T cells, CD28 signaling has been proposed as a T-cell metabolic biosensor 1 . Conversely, CTLA-4 engagement has been shown to down-regulate T-cell glycolysis 1 . Here, we investigated the impact of CTLA-4 blockade on the metabolic fitness of intra-tumor T cells in relationship to the tumor glycolytic capacity. We found that CTLA-4 blockade promotes immune cell infiltration and metabolic fitness especially in glycolysis-low tumors. Accordingly, anti-CTLA-4 achieved better therapeutic outcomes in mice bearing glycolysis-defective tumors. Intriguingly, tumor-specific CD8 + T-cell responses correlated with phenotypic and functional destabilization of tumor-infiltrating regulatory T cells (Tregs) toward IFN-γ- and TNF-α-producing cells in glycolysis-defective tumors. By mimicking the highly and poorly glycolytic TME in vitro , we show that the effect of CTLA-4 blockade to promote Treg destabilization is dependent on Treg glycolysis and CD28 signaling. These findings indicate that decreasing tumor competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumor glycolysis. Moreover, these results reveal a new mechanism through which anti-CTLA-4 interferes with Treg function in the presence of glucose.

OX40 engagement induces a cytotoxic CD4+ T cell subpopulation to eradicate advance melanomas

Ir-based nanomaterials are regarded as state-of-the-art cathode electrocatalysts in proton exchange membrane water electrolyzers (PEMWEs). Engineering the morphology of Ir-based three-dimensional architectures as electrocatalysts toward oxygen evolution reaction (OER) has been rarely studied.Here, we report the gelation of Ir x Cu metallic hydrogels self-assembled with ultrafine and nanovoid incorporated building blocks for enhancing the electrocatalytic performance toward OER. The composition-optimized Ir 3 Cu metallic aerogels exhibited improved catalytic activity and durability toward OER. The mesosized voids generated through the in situ galvanic replacement reaction and the macrosized porous systems make a great contribution to the increased number of active sites. First-principle calculations revealed the intrinsic optimized binding energy of Ir by alloying with Cu. The best catalytic performance necessities a balance of the adsorption and desorption energy. The well-defined morphology and enhanced OER electrochemical performances of nanovoid incorporated Ir x Cu metallic aerogels hold great promise in further applications in PEMWEs.

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A primary goal of cancer immunotherapy is to improve the naturally occurring, but weak, immune response to tumors. Ineffective responses to cancer vaccines may be caused, in part, by low numbers of self-reactive lymphocytes surviving negative selection. Here, we estimated the frequency of CD8+ T cells recognizing a self-antigen to be <0.0001% (∼1 in 1 million CD8+ T cells), which is so low as to preclude a strong immune response in some mice. Supplementing this repertoire with naive antigen-specific cells increased vaccine-elicited tumor immunity and autoimmunity, but a threshold was reached whereby the transfer of increased numbers of antigen-specific cells impaired functional benefit, most likely because of intraclonal competition in the irradiated host. We show that cells primed at precursor frequencies below this competitive threshold proliferate more, acquire polyfunctionality, and eradicate tumors more effectively. This work demonstrates the functional relevance of CD8+ T cell precursor frequency to tumor immunity and autoimmunity. Transferring optimized numbers of naive tumor-specific T cells, followed by in vivo activation, is a new approach that can be applied to human cancer immunotherapy. Further, precursor frequency as an isolated variable can be exploited to augment efficacy of clinical vaccine strategies designed to activate any antigen-specific CD8+ T cells.

Lithium-sulfur (Li-S) batteries have attracted considerable attentions in electronic energy storage and conversion because of their high theoretical energy density and cost effectiveness. The rapid capacity degradation, mainly caused by the notorious shuttle effect of polysulfides (PSs), remains a great challenge preventing practical application. Porous organic polymers (POPs) are one type of promising carbon materials to confine PSs within the cathode region. Here, the research progress on POPs and POPs-derived carbon materials in Li-S batteries is summarized, and the importance of pore surface chemistry in uniform distribution of sulfur and effective trapping of PSs is highlighted. POPs serve as promising sulfur host materials, interlayers, and separators in Li-S batteries. Their significance and innovation, especially new synthetic methods for promoting sulfur content, reversible capacity, Coulombic efficiency and cycling stability, have been demonstrated. The perspectives and critical challenges that need to be addressed for POPsbased Li-S batteries are also discussed. Some attractive electrode materials and concepts based on POPs have been proposed to improve energy density and electrochemical performance, which are anticipated to shed some light on future development of POPs in advanced Li-S batteries. a theoretical capacity of 3840 mA h g −1 , the conventional Li-S batteries could provide an average battery voltage of 2.2 V and a high theoretical energy density of 2570 W h kg −1 , which is 2-3 times higher than practical energy density of the commercial lithium ion batteries (LIBs). [4][5][6] Moreover, low cost, natural abundance, and environmental friendliness of sulfur endow Li-S batteries with great development potential and space compared with LIBs. Despite the overwhelming advantages, the practical application of Li-S batteries suffers from several technological obstacles, such as (i) poor electrical conductivities of sulfur and solid-state discharging products (Li 2 S 2 and Li 2 S); (ii) the dissolution of soluble lithium polysulfides (PSs) intermediates in the electrolytes and their free migration between cathode and anode, which results in notorious shuttle effect of PSs; (iii) huge volume fluctuation (≈80%) of the active materials during discharge and charge owing to large density difference between element sulfur and solid-state products. The major disadvantage is the shuttle effect of PSs among the above problems. During discharge and charge cycle, the dissolved high-order PSs generated in the cathode move toward the anode and react with lithium metal to form low-order PSs or a passive layer on the anode surface, low-order PSs diffuse back to the cathode and produce high-order PSs again. This process usually causes irreversible loss of active materials and low Coulombic efficiency, which are associated with fast capacity fading, low energy efficiency, severe self-discharge, and poor cycling stability. [1,[7][8][9][10] To address these problems, considerable efforts have been devoted to the devel...

Ligation of GITR (glucocorticoid-induced tumor necrosis factor (TNF) receptor-related gene, or TNFRSF18) by agonist antibody has recently entered into early phase clinical trials for the treatment of advanced malignancies. Although the ability of GITR modulation to induce tumor regression is well-documented in preclinical studies, the underlying mechanisms of action, particularly its effects on CD4+foxp3+ regulatory T cells (Treg), have not been fully elucidated. We have previously demonstrated that GITR ligation in vivo by agonist antibody DTA-1 causes a >50% reduction of intra-tumor Treg with down modulation of Foxp3 expression. Here we show that the loss of Foxp3 is tumor-dependent. Adoptively-transferred Foxp3+Treg from tumor-bearing animals lose Foxp3 expression in the host when treated with DTA-1, whereas Treg from naïve mice maintain Foxp3 expression. GITR ligation also alters the expression of various transcription factors and cytokines important for Treg function. Complete Foxp3 loss in intra-tumor Treg correlates with a dramatic decrease in Helios expression and is associated with the upregulation of transcription factors T-Bet and Eomes. Changes in Helios correspond with a reduction in IL-10 and an increase in IFNγ expression in DTA-1-treated Treg. Together, these data show that GITR agonist antibody alters Treg lineage stability inducing an inflammatory effector T cell phenotype. The resultant loss of lineage stability causes Treg to lose their intra-tumor immune suppressive function, making the tumor susceptible to killing by tumor-specific effector CD8+ T cells.