PNP (purine nucleoside phosphorylase) is a cytoplasmic enzyme that catalyzes the phosphorolytic breakdown of the N-glycosidic bond in purine nucleosides, preferentially acting on 6-oxopurine nucleosides including inosine and guanosine to generate free purine bases and pentose-1-phosphate. This enzyme plays a central role in purine salvage metabolism and is particularly abundant in lymphoid tissues. Biallelic loss-of-function mutations in PNP cause severe combined immunodeficiency affecting both T- and B-cell immunity, with approximately two-thirds of patients developing neurological complications ranging from spasticity to developmental delay 1. Elevated deoxyguanosine triphosphate (dGTP) in deficient patients is proposed to inhibit ribonucleotide reductase and impede cell division, while depressed GTP levels may underlie neurologic dysfunction 1. Recent studies reveal PNP's broader metabolic roles in infection and cancer. PNP activation by influenza A virus enhances purine salvage to promote viral replication and pro-inflammatory signaling; inhibiting PNP constrains both outcomes 2. In EGFR-mutant lung adenocarcinoma, reduced PNP activity causes inosine accumulation, activating A2aR signaling and driving tyrosine kinase inhibitor resistance; restoring PNP expression or inhibiting A2aR with taminadenant restores drug sensitivity 3. PNP also bidirectionally constrains telomere length through nucleotide salvage efficiency; the PNP inhibitor ulodesine lengthens telomeres in cells from patients with telomere diseases 4. These findings suggest PNP inhibitors and modulators as therapeutic strategies for infection, malignancy, and telomeropathy.