NME4 is a mitochondrial nucleoside diphosphate kinase that performs dual functions in cellular homeostasis. As a metabolic enzyme, NME4 catalyzes the transfer of gamma-phosphoryl groups from ATP to nucleoside diphosphates via a phosphohistidine intermediate, maintaining nucleoside triphosphate homeostasis in mitochondria 1. The enzyme associates with cardiolipin-containing mitochondrial inner membrane, locally producing ADP that stimulates respiratory ATP regeneration and directly providing GTP for mitochondrial GTPases like OPA1 2. Beyond its kinase activity, NME4 functions as a phospholipid transfer protein, catalyzing cardiolipin transfer between mitochondrial membranes through contact site formation, which is independent of its kinase function 3. This cardiolipin externalization serves as an 'eat me' signal during mitophagy, targeting dysfunctional mitochondria for lysosomal degradation 3. In cancer contexts, NME4 demonstrates complex roles: it acts as a metastasis suppressor by maintaining mitochondrial fusion through OPA1 interaction 2, yet promotes immune evasion by suppressing the NFκB2-CCL5 axis, preventing CD8+ T cell tumor infiltration 4. High NME4 expression correlates with poor prognosis in lung adenocarcinoma and clear cell renal cell carcinoma, particularly in immunotherapy contexts 56.