Targeting Nucleotide Metabolism for Enhancing Antitumor Immunity

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Background

Over the last decade, targeting the immune system with immunotherapy has revolutionized cancer therapy. Tumors have immunogenicity features similar to those of other pathogenic agents while also reserving many specific biological reactions. Modulation of the existing patient immune system through immune checkpoint inhibitors (ICIs) such as anti-CTLA4, anti-PD1 and anti-PDL1 has resulted in durable remissions across different cancer types. Furthermore, infusion of expanded autologous tumor-specific T cells or chimeric antigen receptor T cells has proven effective in patients with leukemia. Nevertheless, this enthusiasm in the field is somewhat tempered by both the relatively low percentage (<15%) of patients who show an effective antitumor immune response and the inability to accurately identify them, suggesting there are additional mechanisms that are important in driving antitumor immunity. This limited efficacy underscores the importance of better understanding the mechanisms underlying the antitumor immune response, and the mechanisms that mediate response to ICIs, as well as identifying additional pathways to modulate it.

Targeting nucleotide metabolism can not only suppress the occurrence and development of tumors, but also exert serious side effects. The understanding of nucleotide metabolism in tumors, along with in-depth research of nucleotide metabolism, has revealed their non-proliferative roles in immune evasion, revealing the potential effectiveness of nucleotide antimetabolites to enhance immunotherapy. Accumulated evidence suggests that targeting nucleotide metabolism can enhance the antitumor immunity by activating host immune system by maintaining the concentrations of several important metabolites (adenosine and ATP, etc.), facilitating immunogenicity induced by increased mutability and genomic instability via disrupting the purine and pyrimidine pool, and releasing nucleoside analogs via microbes to modulate immunity. Therapeutic approaches targeting nucleotide metabolism combined with immunotherapy have achieved exciting success in preclinical studies. However, due to their lack of specificity for tumor cell nucleotide metabolism, current treatment also inhibits the metabolic processes of normal cells, resulting in serious side effects. Therefore, more in-depth research of the regulatory processes of nucleotide metabolism has key theoretical and clinical significance in cancer immunotherapy.

The submissions may refer to the following areas/topics, these are however examples and submissions are not limited to those:

1. Roles and mechanisms of nucleotides in the activation or suppression of innate and adaptive immune responses.
2. Agents targeting nucleotide receptors combined with immunotherapy for cancer treatment.
3. Pyrimidine or purine metabolism dysregulation in gene mutation and tumor immunogenicity.
4. Microbes that can release nucleoside analogs in regulating the immune microenvironment.
5. Nucleotide metabolism in modulating the cancer-immune cycle.
6. Antimetabolites targeting nucleotide metabolism in combination with immunotherapy agents in preclinical and clinical trial studies.
7. Cytotoxic chemotherapy or specific enzyme inhibitors targeting nucleotide metabolism in improving antitumor immune response.
8. Targeting nucleotide metabolism pathways in cancer immunotherapy, such as targeting purine and pyrimidine pathways, blocking DNA synthesis, suppressing the adenosine pathway, and fecal microbiota transplantation.
9. Using computational methods to identify robust genetic and epigenetic biomarkers, gene models, etc. to predict prognosis and antitumor immune response based on multi-omic data.

*NOTE: Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation are considered out of the scope of this Research Topic.

Keywords: nucleotide metabolism, immunotherapy, antitumor immune response, tumor immunogenicity, immune microenvironment

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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