Highlights d AGK is required for CD8 + T cell expansion and antitumor function d AGK regulates CD8 + T cell glycolysis and PI3K-mTOR activation d AGK-triggered PTEN inactivation promotes a CD8 + T cell metabolic switch d TCR-initiated PTEN phosphorylation in CD8 + T cells relies on AGK kinase activity

Background: Branched-chain amino acids (BCAAs), essential nutrients including leucine, isoleucine, and valine, serve as a resource for energy production and the regulator of important nutrient and metabolic signals. Recent studies have suggested that dysfunction of BCAA catabolism is associated with the risk of cardiovascular disease. Platelets play an important role in cardiovascular disease, but the functions of BCAA catabolism in platelets remain unknown. Methods: The activity of human platelets from healthy subjects before and after ingestion of BCAAs was measured. Protein phosphatase 2Cm specifically dephosphorylates branched-chain α-keto acid dehydrogenase and thereby activates BCAA catabolism. Protein phosphatase 2Cm–deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation. Results: We found that ingestion of BCAAs significantly promoted human platelet activity (n=5; P <0.001) and arterial thrombosis formation in mice (n=9; P <0.05). We also found that the valine catabolite α-ketoisovaleric acid and the ultimate oxidation product propionyl-coenzyme A showed the strongest promotion effects on platelet activation, suggesting that the valine/α-ketoisovaleric acid catabolic pathway plays a major role in BCAA-facilitated platelet activation. Protein phosphatase 2Cm deficiency significantly suppresses the activity of platelets in response to agonists (n=5; P <0.05). Our results also suggested that BCAA metabolic pathways may be involved in the integrin αIIbβ3–mediated bidirectional signaling pathway that regulates platelet activation. Mass spectrometry identification and immunoblotting revealed that BCAAs enhanced propionylation of tropomodulin-3 at K255 in platelets or Chinese hamster ovary cells expressing integrin αIIbβ3. The tropomodulin-3 K255A mutation abolished propionylation and attenuated the promotion effects of BCAAs on integrin-mediated cell spreading, suggesting that K255 propionylation of tropomodulin-3 is an important mechanism underlying integrin αIIbβ3–mediated BCAA-facilitated platelet activation and thrombosis formation. In addition, the increased levels of BCAAs and the expression of positive regulators of BCAA catabolism in platelets from patients with type 2 diabetes mellitus are significantly correlated with platelet hyperreactivity. Lowering dietary BCAA intake significantly reduced platelet activity in ob/ob mice (n=4; P <0.05). Conclusions: BCAA catabolism is an important regulator of platelet activation and is associated with arterial thrombosis risk. Targeting the BCAA catabolism pathway or lowering dietary BCAA intake may serve as a novel therapeutic strategy for metabolic syndrome–associated thrombophilia.

Radiation therapy can potentially elicit a systemic immune response and cause the regression of nonirradiated tumors, and the checkpoint blockade immunotherapies have been introduced to improve their clinical response rate. However, the therapeutic benefits of radioimmunotherapy are still far from satisfactory. Herein, the self-assembled “carrier-free” coordination polymer nanorods are constructed based on gadolinium and zoledronic acid, which can deposit X-ray for improved reactive oxygen species production to induce potent immunogenic cell death (ICD), simultaneously deplete tumor-associated macrophages with regulatory cytokines inhibition, respectively. With the potent ICD induction and reprogrammed immunosuppressive microenvironment, this synergetic strategy can promote antigen presentation, immune priming and T-cell infiltration, and potentiate checkpoint blockade immunotherapies against primary, distant, and metastatic tumors.

Electrocaloric effect driven by electric fields displays great potential in realizing highly efficient solid-state refrigeration. Nevertheless, most known electrocaloric materials exhibit relatively poor cooling performance near room temperature, which hinders their further applications. The emerging family of hybrid perovskite ferroelectrics, which exhibits superior structural diversity, large heat exchange and broad property tenability, offers an ideal platform. Herein, we report an exceptionally large electrocaloric effect near room temperature in a designed hybrid perovskite ferroelectric [(CH3)2CHCH2NH3]2PbCl4, which exhibits a sharp first-order phase transition at 302 K, superior spontaneous polarization (>4.8 μC/cm2) and relatively small coercive field (<15 kV/cm). Strikingly, a large isothermal entropy change ΔS of 25.64 J/kg/K and adiabatic temperature change ΔT of 11.06 K under a small electric field ΔE of 29.7 kV/cm at room temperature are achieved, with giant electrocaloric strengths of isothermal ΔS/ΔE of 0.86 J·cm/kg/K/kV and adiabatic ΔT/ΔE of 370 mK·cm/kV, which is larger than those of traditional ferroelectrics. This work presents a general approach to the design of hybrid perovskite ferroelectrics, as well as provides a family of candidate materials with potentially prominent electrocaloric performance for room temperature solid-state refrigeration.