As a stimulator of interferon gene (STING), cyclic dinucleotide activates a broad cellular immune response for anti‐cancer immunotherapy (CIT). However, the inherent of instability of 2′ 3′‐cyclic‐GMP‐AMP (cGAMP) with poor cellular targeting, rapid clearance, and inefficient transport to the cytoplasm seriously hinders cGAMP potency. Here, a thiolated and Mn2+ coordinated cyclic dinucleotide nanovaccine (termed as Mn‐cGAMP NVs) to enable direct cytosolic co‐delivery of cGAMP and Mn2+ to potentiate the antitumor immune response is presented. In the NVs, the fixation cGAMP with Mn2+ ions not only improve its stability, but also potentiate the activation of STING. Meanwhile, the presence of polysulfides on the NVs surface allowed direct cytosolic delivery while avoiding degradation. In this way, the production of cytokines for activating T cells immunity is greatly elevated, which in turn suppressed the primary and distal tumors growth through long‐term immune memory and led to long‐term survival of poorly immunogenic B16F10 melanoma mice. Moreover, by further combining with anti‐PD‐L1 monoclonal antibody, synergistic T cells antitumor immune response is elicited. This work offers a promising strategy to enhance the potency of cGAMP, holding a considerable potential for CIT applications.

No abstract

No abstract

Peroxisome proliferator-activated receptor a (PPARa) is a member of the nuclear receptor family, regulating fatty acid degradation in many organs. Two-dimensional SDS-PAGE of brown adipose tissue (BAT) from PPARa-null mice produced a higher-density spot. Proteomic analysis indicated that the protein was pyruvate dehydrogenase b (PDHb). To observe PDHb regulation in BAT, the organ was stimulated by long-term cold exposure, and the activities of associated enzymes were investigated. Histological and biochemical analyses of BAT showed a significant decrease in the triglyceride content in wild-type mice and some degree of decrease in PPARa-null mice on cold exposure. Analyses of molecules related to glucose metabolism showed that the expression of PDHb is under PPARa-specific regulation, and that glucose degradation ability may decrease on cold exposure. In contrast, analyses of molecules related to fatty acid metabolism showed that numerous PPARa ⁄ c target molecules are induced on cold exposure, and that fatty acid degradation ability in wild-type mice is markedly enhanced and also increases to same degree in PPARa-null mice on cold exposure. Thus, this study proposes novel and multiple roles of PPARa in BAT.

No abstract