Pyruvate kinase (PK), as one of the key enzymes for glycolysis, can encode four different subtypes from two groups of genes, although the M2 subtype PKM2 is expressed mainly during embryonic development in normal humans, and is closely related to tissue repair and regeneration, with the deepening of research, the role of PKM2 in tumor tissue has received increasing attention. PKM2 can be aggregated into tetrameric and dimeric forms, PKM2 in the dimer state can enter the nuclear to regulate gene expression, the transformation between them can play an important role in tumor cell energy supply, epithelial–mesenchymal transition (EMT), invasion and metastasis and cell proliferation. We will use the switching effect of PKM2 in glucose metabolism as the entry point to expand and enrich the Warburg effect. In addition, PKM2 can also regulate each other with various proteins by phosphorylation, acetylation and other modifications, mediate the different intracellular localization of PKM2 and then exert specific biological functions. In this paper, we will illustrate each of these points.

In the publication of this article [1], there is an error in Figure 7a and 7b. This has now been included in this correction.

The clinical benefit of immunotherapy for hepatocellular carcinoma (HCC) is often limited by innate immune tolerance. Traditional research focuses on the intrinsic escape mechanism of tumor cells or the generalized immunosuppression of the tumor microenvironment; however, it often ignores the chronic liver disease background of HCC patients with different etiologies. The aim of this review was to systematically discuss the mechanisms by which different underlying liver diseases, particularly metabolic dysfunction associated steatohepatitis, viral hepatitis (hepatitis B virus/hepatitis C virus) and alcoholic liver disease, specifically shape the liver immune microenvironment, thereby driving HCC to develop tolerance to immune checkpoint inhibitors. We further explored the molecular mechanisms by which various etiologies promote T cell exhaustion, expand immunosuppressive cells, and change the function of the gut-liver axis through unique pathways, such as metabolic dysfunction-associated steatohepatitis-related metabolic disorders and dysbiosis, sustained antigen stimulation and epigenetic regulation of viral hepatitis, and the hyperinflammatory chemokine network of alcoholic liver disease. In addition, this article systematically evaluates the potential synergistic or antagonistic effects of drugs used to treat these underlying liver diseases (e.g., lipid-lowering drugs, liver protective drugs, antiviral drugs, antifibrotic drugs, and new metabolic targeted drugs) on HCC immunotherapy. The objectives are to provide key mechanistic insights and strategic references for clinical combination drugs, as well as emphasize the corresponding individualized immunotherapy strategies for HCC caused by different diseases.

Background: Colorectal cancer (CRC) is the most common malignant tumor of the digestive tract worldwide, however, the potential targets for CRC and its subsites (colon cancer & rectum cancer) are less known. The aim of this study is to explore potential therapeutic targets for CRC. Methods: A proteome-wide genome-wide association studies (GWAS) in 35,559 Icelanders with 4,907 plasma proteins was used as instrumental variables (P value <5×10⁻⁸). The discovery stage consisted of the CRC GWAS with the largest sample size (CRC: 14,886 cases; colon: 3,793 cases; rectum: 2,091 cases). The significant proteins were further validated in the FinnGen study with 5,458 CRC cases (3,292 colon + 2,017 rectum). We identified relevant protein loci in CRC by two sample Mendelian randomization (MR) [false discovery rate (FDR) <0.05], colocalization analysis was used to further determine the relevance between CRC and plasma proteins, enrichment analysis and drug prediction were used to predict protein function. Results: A total of 31 proteins were found to be in robust causal associations with CRC and the proteins’ effects displayed anatomic site-specificity in MR analysis. The subsequent colocalization analysis pinpointed that CHDRL2 had a shared region with CRC and its two subsites, suggesting the importance of targeting it. Besides, IGF2R and ENPEP displayed anatomic site-specificity to colon cancer while ASRGL1 was strongly correlated only with the risk of rectal cancer. Enrichment analysis revealed functions of these proteins in CRC, and DrugBank showed their target drug. Conclusions: In summary, our study has identified a common protein, CHDRL2, as the drug targets for CRC and its subsites. Besides, IGF2R and ENPEP displayed anatomic site-specificity to colon cancer while ASRGL1 was strongly correlated only with the risk of rectal cancer.