Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy

Abstract

Targeting nucleotide metabolism can not only inhibit tumor initiation and progression but also exert serious side effects. With in-depth studies of nucleotide metabolism, our understanding of nucleotide metabolism in tumors has revealed their non-proliferative effects on immune escape, indicating the potential effectiveness of nucleotide antimetabolites for enhancing immunotherapy. A growing body of evidence now supports the concept that targeting nucleotide metabolism can increase the antitumor immune response by (1) activating host immune systems via maintaining the concentrations of several important metabolites, such as adenosine and ATP, (2) promoting immunogenicity caused by increased mutability and genomic instability by disrupting the purine and pyrimidine pool, and (3) releasing nucleoside analogs via microbes to regulate immunity. Therapeutic approaches targeting nucleotide metabolism combined with immunotherapy have achieved exciting success in preclinical animal models. Here, we review how dysregulated nucleotide metabolism can promote tumor growth and interact with the host immune system, and we provide future insights into targeting nucleotide metabolism for immunotherapeutic treatment of various malignancies.

Fig. 1

Historical development and breakthroughs in targeting nucleotide metabolism in cancer treatment. Targeting nucleotide metabolism in cancer treatment could be divided into two generations. In the Generation 1, targeting nucleotide metabolism was designed as chemotherapeutics to treat cancer. In the Generation 2, immunotherapy could enhance its efficacy with therapeutic agents blocking nucleotide metabolism

Fig. 2

Interactions between nucleotide metabolism and host immunity. Cancer cells could release metabolites from nucleotide metabolism, such as ATP, adenosine to A Regulate immunoregulatory cells through adenosine and purinergic receptors; B In cancer cells, disrupted nucleotide pool could raise tumor immunogenicity; C Microbes release nucleoside analogs to regulate immunity. A2AR adenosine 2A receptor, P2X purinergic P2X receptor, P2Y purinergic P2Y receptor, TLRs Toll-like receptors, CD39 ecto-nucleoside triphosphate diphosphohydrolase-1, CD73 ecto-5-nucleotidase, M2 M2-type macrophage, MICA major histocompatibility complex class I-related chain A, NFAT nuclear factor of activated T cells, PTMB pyrimidine-rich transversion mutational bias, TAM tumor-associated macrophage

Fig. 3

Therapeutic strategies to exploit the nucleotide metabolism–immunity interplay in the clinic. A Targeting purine or pyrimidine pathways; B blocking DNA synthesis; C inhibiting adenosine pathway; D fecal microbiota transplantation. CAD carbamoyl phosphate synthetase, aspartyl transcarbamoylase, and dihydroorotase, IMPDH inosine monophosphate dehydrogenase, MDSCs myeloid-derived suppressive cells, A2AR adenosine 2A receptor, CD39 ecto-nucleoside triphosphate diphosphohydrolase-1, ASOs antisense oligonucleotides, CD73 ecto-5-nucleotidase