The microenvironment in cancerous tissues is immunosuppressive, whereas the microenvironment of tissues affected prognosis of immunotherapy. Although these opposing immunological states, the metabolic states in the tumor microenvironments and inflammatory diseases are similar, which show elevated levels of metabolic by-products while have low levels of nutrients compared with normal tissues. A clear understanding of the metabolic signature of HCC will enable therapeutic intervention aimed at reprograming the bioavailability of metabolites and modulating the dysregulated immunological state, promoting the immunotherapy
[197][74]. As discussed above, reprograming of TAMs was widely developed for HCC therapy. Recent investigations have indicated that metabolism profiles manipulate phenotypes and functions of macrophages. On the contrary, polarization can trigger metabolic shifts in macrophages. Those discovery implicate a special role of metabolism in TAMs, and it can be target for the promotion of immunotherapy
[198][75]. The research of immune metabolism has revealed that metabolic changes can result in anti-cancer immunity. Correspondingly, combination therapies with metabolic inhibitors and antibodies of immune checkpoint blockade have shown exciting results. The Rathmell lab developed strategies to shift immune cell metabolism to tune TIME, and finally to enhance immunotherapy
[199][76]. Regulatory T cells (Tregs) are a subset of T cells that contribute to immunosuppressive effects in tumor microenvironment, which can promote differentiation, proliferation, secretion of immunosuppressive factors, and chemotactic recruitment of Tregs to play crucial role in immunosuppression in tumor tissues. The cell metabolism reprogramming is relative to the functional effects on Tregs. Therefore, it’s important to well understand the role of cell metabolism on the TIME for HCC immunotherapy
[200][77]. The knowledge from extensive research in immune metabolism shows that targeting metabolism could help to enhance antitumor immunity
[201][78]. The Locasale lab developed a computational pipeline to study metabolic programs in single cells to define the intratumor metabolic landscape. They found the expression of both glycolytic and mitochondrial network strongly correlates with hypoxia in all cell types, especially the immune cells
[202][79]. Metabolic pathways could modulate the TIME and mitochondrial metabolism, which are an attractive target for cancer immunotherapy. Rosner lab have verified that BTB and CNC homology1 targets mitochondrial metabolism
[203][80]. Glycolysis level correlates with immune activity in TIME, while the systematic investigation of the relevance between tumor glycolysis and tumor immunity in various tumor remains scarce. Jiang and co-authors have found glycolytic activity enhances PD-L1 expression on tumor cells, and subsequently promotes the response of anti-PD-1/PD-L1 immunotherapy
[204][81]. Targeted delivery of therapeutics to mitochondria remains a great challenge due to their location in the sub-cellular compartment and complexity of the intracellular environment. Jiang and co-authors have reported a class of mitochondrion-targeted liposomal delivery carriers, which exhibits about 3.7-fold higher mitochondrion-targeted delivery efficacy than current triphenylphosphonium
[205][82]. Metabolism regulation of tumor and simultaneously modulating the TIME to perform immune attack are significant for cancer prevention. Liu and co-authors have developed a novel drug vector to inhibit glycolysis of cancer cells and mitigate the immunosuppressive microenvironment
[206][83]. Chaudhary and co-authors have reviewed recent literatures on metabolic reprogramming and associated signaling pathways that mediate crosstalk of tumor with immune cells
[207][84]. As shown in
Figure 6, they have provided a scheme as to metabolic crosstalk of tumor and immune cells in tumor microenvironment. Although they mainly discussed in oral squamous cell carcinoma, while it’s a good reference for HCC.