High expression of programmed death-ligand-1 (PD-L1) in hepatocellular carcinoma (HCC) cells usually inhibits the proliferation and functions of T cells, leading to immune suppression in tumor microenvironment. However, very little has been described regarding the mechanism of PD-L1 overexpression in HCC cells. In the present study, we found epidermal growth factor (EGF) stimulation promoted the expression of PD-L1 mRNA and protein in HCC cells. Inhibition of epidermal growth factor receptor (EGFR) could reverse EGF-induced the expression of PD-L1 mRNA and protein. Subsequently, we also observed that the phosphorylation level of Pyruvate kinase isoform M2 (PKM2) at Ser³⁷ site was also increased in response to EGF stimulation. Expression of a phosphorylation-mimic PKM2 S37D mutant stimulated PD-L1 expression as well as H3-Thr¹¹ phosphorylation in HCC cells, while inhibition of PKM2 significantly blocked EGF-induced PD-L1 expression and H3-Thr¹¹ phosphorylation. Furthermore, mutation of Thr¹¹ of histone H3 into alanine abrogated EGF-induced mRNA and protein expression of PD-L1, Chromatin immunoprecipitation (ChIP) assay also suggested that EGF treatment resulted in enhanced H3-Thr¹¹ phosphorylation at the PD-L1 promoter. In a diethylnitrosamine (DEN)-induced rat model of HCC, we found that the expression of phosphorylated EGFR, PKM2 nuclear expression, H3-Thr¹¹ phosphorylation as well as PD-L1 mRNA and protein was higher in the livers than that in normal rat livers. Taken together, our study suggested that PKM2-dependent histone H3-Thr¹¹ phosphorylation was crucial for EGF-induced PD-L1 expression at transcriptional level in HCC. These findings may provide an alternative target for the treatment of hepatocellular carcinoma.

Platinum (Pt) drugs have developed rapidly in clinical applications because of their broad and highly effective antitumor effects. In recent years, with the rapid development of immunotherapy, Pt-based antitumor agents have gained new challenges and opportunities. Since the discovery of their pharmacological effects in immunotherapy and tumor microenvironment regulation, research into Pt drugs has progressed to multi-ligand and multi-functional Pt precursors and their own shortcomings have been further highlighted. With the development of antitumor immunotherapy and the rise of combination therapy, the development of Pt-based drugs has started to move in the direction of multi-targeting, nanocarrier modification, immunotherapy and photodynamic therapy. In this paper, we first overview the recent applications of Pt-based drugs in antitumor inorganic chemistry, with a focus on summarizing the application of Pt-based drugs and their precursors in the anticancer immune response. The paper also provides a reasonable outlook on the future development of Pt-based drugs from the chemical and immunological perspectives, relying on the existing content and problems of Pt-based drug development. On the basis of the gathered information, joint multidisciplinary programs on implementing comprehensive immune analyses for the future development of novel anticancer metal compounds should be initiated.

Corrigendum: PKM2-Induced the Phosphorylation of Histone H3 Contributes to EGF-Mediated PD-L1 Transcription in HCC

Structures containing galactose and GalNAc residues are specifically recognized by asialoglycoprotein receptors, allowing them to selectively internalize by hepatocytes for drug-targeting delivery. However, methods for direct synthesis of GalNAc glycosides are still challenging due to the poor participating group of 2-acetamido. Here, we develop a facile strategy to synthesize various GalNAc glycosides by employing a series of rare earth metal triflates, and the results demonstrate that both α-glycosides and β-glycosides of GalNAc can be obtained by conducting with Hf(OTf)₄ and Sc(OTf)₃, respectively. These applicable results indicate that any interested GalNAc-containing substrates could be prepared by this simple strategy.