Research progress of abnormal lactate metabolism and lactate modification in immunotherapy of hepatocellular carcinoma

Abstract

Tumors meet their energy, biosynthesis, and redox demands through metabolic reprogramming. This metabolic abnormality results in elevated levels of metabolites, particularly lactate, in the tumor microenvironment. Immune cell reprogramming and cellular plasticity mediated by lactate and lactylation increase immunosuppression in the tumor microenvironment and are emerging as key factors in regulating tumor development, metastasis, and the effectiveness of immunotherapies such as immune checkpoint inhibitors. Reprogramming of glucose metabolism and the “Warburg effect” in hepatocellular carcinoma (HCC) lead to the massive production and accumulation of lactate, so lactate modification in tumor tissue is likely to be abnormal as well. This article reviews the immune regulation of abnormal lactate metabolism and lactate modification in hepatocellular carcinoma and the therapeutic strategy of targeting lactate-immunotherapy, which will help to better guide the medication and treatment of patients with hepatocellular carcinoma.

Histomolecular characterisation of hepatitis B virus induced liver cancer

“…The large generation and buildup of lactate caused by the resetting of glucose metabolism in (HCC) suggests that lactate modulation in the cancerous cells is also expected to be aberrant. 42 According to a worldwide prospective cohort study on lactylome sequencing in patients with HBV-related HCC, Lysine lactylation (Kla) is a common alteration that extends over the realm of histone proteins and transcriptional oversight, as shown by the 9275 Kla sites that were found in the cancers and neighbouring livers after an integrated lactylome and proteome study. Of these sites, 9256 were on non-histone enzymes.…”

“…The growth of tumours, the spread of cancer, and the efficiency of immunotherapies such immune checkpoint inhibitors are all being influenced by immune cell remodelling and cellular elasticity, which is facilitated by lactate and lactylation. The large generation and buildup of lactate caused by the resetting of glucose metabolism in (HCC) suggests that lactate modulation in the cancerous cells is also expected to be aberrant 42 …”

Al-Hijamah (Prophetic Wet Cupping Therapy) is a Novel Adjuvant Treatment for Viral Hepatitis That Excretes Viral Particles and Excess Ferritin Percutaneously, Synergizes Pharmacotherapy, Enhances Antiviral Immunity and Helps Better HCC Prevention and Treatment: A Novel Evidence-Based Combination with Prophetic Medicine Remedies

“…Note: Data from El-Shanshory et al 18 Journal of Hepatocellular Carcinoma 2023:10 Other viral diseases like AIDS can benefit from the same treatment advantages. Al-hijamah is absolutely necessary for the excretion and removal of CPS that promote cancer, such as lactate (the Warburg effect), 41 growth factors, metalloproteinases, and others, even after cancer (as HCC) has developed. 13 Immune potentiation brought on by al-hijamah is very beneficial to cancer patients as HCC.…”

“…16,39,40 Based on Taibah theory, CPS for hepatitis patients include the high serum viral particles, viral nucleic acids, free radicals (reactive oxygen species), inflammatory mediators, ferritin and immune complexes. CPS for HCC patients include the high serum tumor cells' products as massive lactate production (Warburg effect), 41 metalloproteinase (MMP) enzymes (facilitating invasion and metastasis), vascular endothelial growth factor (facilitating angiogenesis), exosomes, free radicals (reactive oxygen species and reactive nitrogen species), and others. Among the MMP family, only MMP1, MMP3, MMP8, MMP9, MMP11, MMP12, MMP14, MMP15, MMP20, MMP21, and MMP24 significantly increased in HCCs compared with adjacent tissues.…”

Development and Validation of a Novel Nomogram Integrated with Hypoxic and Lactate Metabolic Characteristics for Prognosis Prediction in Hepatocellular Carcinoma

“…Increasing evidence suggests that intra-tumoral lactate is a critical regulator that induces the immunosuppressive microenvironment and promotes tumor growth rather than being just a mere metabolic waste. [16][17][18][19] Lactate confers HCC cells with ferroptosis resistance by elevating the levels of antiferroptosis monounsaturated fatty acids and contributes to enhanced proliferation of tumor cells. 20 Intracellular lactate facilitates the proliferation, self-renewal and migration of HCC stem cells by driving the lactylation of H3 histone at K9 and K56.…”