SUMMARY
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca2+-NFAT signaling and effector functions by repressing sarco/ER Ca2+-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy.
Two-inch-sized perovskite crystals, CH3 NH3 PbX3 (X=I, Br, Cl), with high crystalline quality are prepared by a solution-grown strategy. The availability of large perovskite crystals is expected to transform its broad applications in photovoltaics, optoelectronics, lasers, photodetectors, LEDs, etc., just as crystalline silicon has done in revolutionizing the modern electronics and photovoltaic industries.
Endowing materials with specific functions that are not readily available is always of great importance, but extremely challenging. Co N, with its beneficial metallic characteristics, has been proved to be highly active for the oxidation of water, while it is notoriously poor for catalyzing the hydrogen evolution reaction (HER), because of its unfavorable d-band energy level. Herein, we successfully endow Co N with prominent HER catalytic capability by tailoring the positions of the d-band center through transition-metal doping. The V-doped Co N nanosheets display an overpotential of 37 mV at 10 mA cm , which is substantially better than Co N and even close to the benchmark Pt/C catalysts. XANES, UPS, and DFT calculations consistently reveal the enhanced performance is attributed to the downshift of the d-band center, which helps facilitate the H desorption. This concept could provide valuable insights into the design of other catalysts for HER and beyond.
Summary
S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) link
one-carbon metabolism to methylation status. However it is unknown whether
regulation of SAM and SAH by nutrient availability can be directly sensed to
alter the kinetics of key histone methylation marks. We provide evidence that
the status of methionine metabolism is sufficient to determine levels of histone
methylation by modulating SAM and SAH. This dynamic interaction led to rapid
changes in H3K4me3, altered gene transcription, provided feedback regulation to
one-carbon metabolism and could be fully recovered upon restoration of
methionine. Modulation of methionine in diet led to changes in metabolism and
histone methylation in liver. In humans, methionine variability in fasting serum
was commensurate with concentrations needed for these dynamics and could be
partly explained by diet. Together these findings demonstrate that flux through
methionine metabolism and the sensing of methionine availability may allow for
direct communication to the chromatin state in cells.
This work deciphers the modulation essence of p bands on Li-S chemistry by systematically studying the kinetic behaviors of Li-S chemistry on Co-based compounds with fixed metal cation and varied non-metal anions. The p bands originated from the non-metal anions can benefit the interfacial charge interaction by tuning the electron energy of the valence band, endowing S@rGO/CoP with unprecedented rate performance for Li-S batteries. It offers a new vision to rationally design highly efficient materials for Li-S batteries.
Poorly organized tumour vasculature often results in areas of limited nutrient supply and hypoxia. Despite our understanding of solid tumour responses to hypoxia, how nutrient deprivation regionally affects tumour growth and therapeutic response is poorly understood. Here, we show the core region of solid tumours displayed glutamine deficiency compared to other amino acids. Low glutamine in tumour core regions led to dramatic histone hyper-methylation due to decreased α-ketoglutarate levels, a key cofactor for the Jumonji-domain containing (JmjC) histone demethylases (JHDMs). Using patient-derived V600EBRAF melanoma cells, we found that low glutamine-induced histone hyper-methylation resulted in cancer cell de-differentiation and resistance to BRAF inhibitor treatment, which was largely mediated by methylation on H3K27, as knockdown of the H3K27-specific demethylase KDM6B and methyltransferase EZH2 respectively reproduced and attenuated the low glutamine effects in vitro and in vivo. Thus, intra-tumoural regional variation in the nutritional microenvironment contributes to tumour heterogeneity and therapeutic response.
A paradox of tumor immunology is that tumor-infiltrating lymphocytes are dysfunctional in situ, yet are capable of stem cell–like behavior including self-renewal, expansion, and multipotency, resulting in the eradication of large metastatic tumors. We find that the overabundance of potassium in the tumor microenvironment underlies this dichotomy, triggering suppression of T cell effector function while preserving stemness. High levels of extracellular potassium constrain T cell effector programs by limiting nutrient uptake, thereby inducing autophagy and reduction of histone acetylation at effector and exhaustion loci, which in turn produces CD8+ T cells with improved in vivo persistence, multipotency, and tumor clearance. This mechanistic knowledge advances our understanding of T cell dysfunction and may lead to novel approaches that enable the development of enhanced T cell strategies for cancer immunotherapy.
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