New strategies for combined with immunotherapy of clear cell renal cell carcinoma: advances in aerobic glycolysis

Abstract

The incidence of renal malignancies is increasing each year. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of all renal malignancies. Its unique genetic background and mutation features involve dysregulation of homeostasis within the tumor microenvironment (TME) represented by pathways such as hypoxic signaling, glycolytic metabolism, amino acid metabolism, and mitochondrial oxidative phosphorylation. Immune checkpoint inhibitor (ICI) in combination with tyrosine kinase inhibitor (TKI) has become the first line of treatment for patients with advanced ccRCC. However, the efficacy of combination therapy has yet to be improved, and there is an urgent need for biomarkers that can assist the diagnosis, treatment, and prognosis. Multi-omics studies have investigated aberrant abnormalities in molecular pathways of ccRCC in recent years. The ccRCC undergoes metabolic reprogramming and prefers inefficient glycolysis as a significant energy source even under normoxia to support unlimited proliferation. In addition, abnormalities in the aerobic glycolytic pathway have been associated with poor prognosis. Dysregulated glycolytic signaling promotes tumor progression and interacts with immune cells within the TME in ccRCC, resulting in an imbalance between pro and antitumor immunity, creating a suppressive immune microenvironment, promoting tumor immune escape, and impairing antitumor effects of immunotherapy. Therefore, integrating the aerobic glycolytic pathway and the immune microenvironment as an entry point, limiting tumor progression by restricting aberrant glycolytic metabolism broadens therapeutic options for ccRCC and pan-cancer treatments. However, further research is required on maximizing the metabolic reprogramming that tumor cells harbor in the complex TME to convert it into a therapeutic target and apply it in clinical practice. Glycolytic inhibitors in combination with ICI or TKI might be a novel strategy that demonstrates synergistic antitumor effects and overcomes resistance in treating human cancers. This review analyzes the correlations between essential rate-limiting enzymes, transporters, glycolytic pathway inhibitors, and the tumor immune microenvironment in ccRCC. Then we summarize the effects of glycolytic inhibitors in human cancers and alterations in the tumor immune microenvironment. Along with the potential clinical translational value in combination with targeted therapy or immunotherapy, targeting glycolysis will provide new insights for the clinical treatment of ccRCC and bring clinical benefits to patients in the future.

Keywords

• |clear cell renal cell carcinoma|glycolysis|metabolic reprogramming|tumor microenvironment|immunotherapy