Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives.

Hepatocellular carcinoma (HCC) is a major health concern worldwide, with limited therapeutic options and poor prognosis. In recent years, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. The combination treatments based on ICIs have been the major trend in this area. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective treatment for advanced HCC. However, the majority of HCC patients obtain limited benefits. Understanding the immunological rationale and exploring novel ways to improve the efficacy of immunotherapy has drawn much attention. In this review, we summarize the latest progress in this area, the ongoing clinical trials of immune-based combination therapies, as well as novel immunotherapy strategies such as chimeric antigen receptor T cells, personalized neoantigen vaccines, oncolytic viruses, and bispecific antibodies.

Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression.

Protein lysine crotonylation has been recently identified as a vital posttranslational modification in cellular processes, particularly through the modification of histones. We show that lysine crotonylation is an important modification of the cytoplastic and mitochondria proteins. Enzymes in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamine metabolism, glutathione metabolism, the urea cycle, one-carbon metabolism, and mitochondrial fusion/fission dynamics are found to be extensively crotonylated in pancreatic cancer cells. This modulation is mainly controlled by a pair of crotonylation writers and erasers including CBP/p300, HDAC1, and HDAC3. The dynamic crotonylation of metabolic enzymes is involved in metabolism regulation, which is linked with tumor progression. Interestingly, the activation of MTHFD1 by decrotonylation at Lys354 and Lys553 promotes the development of pancreatic cancer by increasing resistance to ferroptosis. Our study suggests that crotonylation represents a metabolic regulatory mechanism in pancreatic cancer progression.