Metabolic Interplay in the Tumor Microenvironment: Implications for Immune Function and Anticancer Response

Abstract

Malignant tumors exhibit rapid growth and high metabolic rates, similar to embryonic stem cells, and depend on aerobic glycolysis, known as the “Warburg effect”. This understanding has enabled the use of radiolabeled glucose analogs in tumor staging and therapeutic response assessment via PET scans. Traditional treatments like chemotherapy and radiotherapy target rapidly dividing cells, causing significant toxicity. Despite immunotherapy’s impact on solid tumor treatment, gaps remain, leading to research on cancer cell evasion of immune response and immune tolerance induction via interactions with the tumor microenvironment (TME). The TME, consisting of immune cells, fibroblasts, vessels, and the extracellular matrix, regulates tumor progression and therapy responses. TME-targeted therapies aim to transform this environment from supporting tumor growth to impeding it and fostering an effective immune response. This review examines the metabolic disparities between immune cells and cancer cells, their impact on immune function and therapeutic targeting, the TME components, and the complex interplay between cancer cells and nontumoral cells. The success of TME-targeted therapies highlights their potential to achieve better cancer control or even a cure.

A cuproptosis-related gene DLAT as a novel prognostic marker and its relevance to immune infiltration in low-grade gliomas

“…According to the findings mentioned above, cuproptosis could serve as a target for cancer treatment. The Warburg effect, or aerobic glycolysis, is thought to be a sign of the spread and cancer progression [ 14 ]. It remains unclear, though, whether increased glycolysis is a contributing factor to or a result of the development of cancer [ 15 ].…”

Editorial: Targeting nucleotide metabolism for enhancing antitumor immunity

“…Nucleotides are major components of genetic material and are essential for DNA and RNA biosynthesis, cell signaling, enzyme regulation, and metabolism ( 8 ). Malignancies exhibit rapid growth and rely more on de novo synthesis than external sources ( 9 ), with very high nucleotide requirements. Immune cells in the TME, especially effector T cells, require rapid expansion when the immune response is activated, as well as lots of nucleotides in order to replicate ( 10 ).…”

“…and Youssef et al. in the manuscript described the effects of interventions including targeting nucleotide pathways on the cellular components of the tumor microenvironment ( 9 , 10 ).…”

“…Studies have shown that aberrant nucleotide metabolism not only accelerates tumor development, but also suppresses normal immune responses (14)(15)(16)(17). Studies have demonstrated that targeting nucleotide metabolism can increase anti-tumor immune responses through multiple pathways (8,9). Such as activating the host immune system by maintaining the concentration of several important metabolites, such as adenosine and ATP; The imbalance of purine/pyrimidine ratio leads to an increase in tumor mutation burden (TMB), which leads to an increase in surface neoantigen expression, thus enhancing immunotherapy.…”

“…It is not well understood how other cell types influence metabolic cancer therapy in the context of the tumor microenvironment. Hyrossova et al and Youssef et al in the manuscript described the effects of interventions including targeting nucleotide pathways on the cellular components of the tumor microenvironment (9,10).…”