Mechanism research and treatment progress of NAD pathway related molecules in tumor immune microenvironment

Abstract

Nicotinamide adenine dinucleotide (NAD) is the core of cellular energy metabolism. NAMPT, Sirtuins, PARP, CD38, and other molecules in this classic metabolic pathway affect many key cellular functions and are closely related to the occurrence and development of many diseases. In recent years, several studies have found that these molecules can regulate cell energy metabolism, promote the release of related cytokines, induce the expression of neoantigens, change the tumor immune microenvironment (TIME), and then play an anticancer role. Drugs targeting these molecules are under development or approved for clinical use. Although there are some side effects and drug resistance, the discovery of novel drugs, the development of combination therapies, and the application of new technologies provide solutions to these challenges and improve efficacy. This review presents the mechanisms of action of NAD pathway-related molecules in tumor immunity, advances in drug research, combination therapies, and some new technology-related therapies.

Construction and validation of a novel NAD+ metabolism‐related risk model for prognostic prediction in osteosarcoma

“…protumor immune cells involve myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). 12,34 Metabolic reprogramming of tumor cells is one adaptation to hypoxia, and the large amount of ATP generated by the Warburg effect for functional operation cannot be separated from the accelerated anabolism of NAD by tumor cells to maintain its high level. 15,35,36 The de novo pathway, salvage pathway, as well as Preiss-Handler (P-H) pathway together constitute the three major pathways of mammalian metabolism of NAD + .…”

“…37 It needs to be emphasized that the specific pathway for NAD + synthesis by tumor cells relies on the normal tissue from the tumor and relies mainly on the P-H pathway and salvage pathway. 12 In both of these pathways, NAPRT, as well as NAMPT, are the key ratelimiting enzymes that carry out anabolic regulation, while another task of the salvage pathway lies in the dependence on three classes of NAD + -consuming enzymes, including NAD + hydrolases (like CD38), sirtuins, and polymerases (PARP), to recycle NAD + . 12,38 Notably, our study combined as many upstream NMRGs of these key enzymes as possible for more stable modeling.…”

“…12 In both of these pathways, NAPRT, as well as NAMPT, are the key ratelimiting enzymes that carry out anabolic regulation, while another task of the salvage pathway lies in the dependence on three classes of NAD + -consuming enzymes, including NAD + hydrolases (like CD38), sirtuins, and polymerases (PARP), to recycle NAD + . 12,38 Notably, our study combined as many upstream NMRGs of these key enzymes as possible for more stable modeling. In the TIME, dysregulation of intracellular synthetic and catabolic metabolism leads to abnormal accumulation of NAD + to promote immune escape and malignant proliferation of tumor cells.…”

“…24 Besides, NAMPT has both intraand extracellular forms, with eNAMPT being its extracellular form. 12 Previous studies have shown that under hypoxia and mechanical stress, eNAMPT exerts one damage-associated molecular pattern protein (DAMP) effect and promotes eNAMPT/toll-like receptor 4 (TLR4) binding to stimulate inflammatory signaling, which significantly increases the production of tumor-supporting M2 macrophages. 39,40 Recently, eNAMPT has been demonstrated in OS, 41 glioblastoma, 11 gastric cancer, 42 and pancreatic cancer 43 by modulating the TIME to promote EMT and malignant proliferation.…”

“…11 The interplay of tumor cells, various immune cells, as well as associated cytokines with signaling pathways jointly constructs the tumor immune microenvironment (TIME) of the body, thus weakening the antitumor function of immune cells to provide an environment beneficial to tumor growth. 12 Dysregulation of intracellular levels of nicotinamide adenine dinucleotide (NAD + ), one crucial regulator of signaling pathways and energy metabolism, profoundly affects DNA damage repair, cell cycle progression, and epigenetic regulation. 13,14 In the TIME, the malignant proliferation of tumor cells is highly dependent on energy metabolism, suggesting the need for accelerated NAD + metabolism.…”