This study aims to investigate how Porphyromonas gingivalis (P. g) secreted nucleoside diphosphate kinase (NDK) affects the tumor-related biological behaviors of oral squamous cell carcinoma (OSCC) cells through NDK-ATP-P2X7 signal axis.An in vitro co-culture model that includes human OSCC cell lines (SCC 9 and SCC 25) together with P. g (W83 strain) and its NDK knockout variant (P. g-△NDK) were established to perform various key experiments to evaluate multiple malignant phenotypes, as well as analyze the relationship between adenosine triphosphate (ATP) and purinergic ligand-gated ion channel 7 (P2X7) receptor.In OSCC tissues, the levels of P. g and P2X7 were significantly higher than those found in adjacent normal tissues (P < 0.0001). In cytological experiments, SCC9 and SCC25 cells infected with P. g exhibited enhanced proliferation, migration, and invasion capabilities (P < 0.0001), increased cytotoxicity (P < 0.0001), and decreased extracellular ATP content (P < 0.001). After infection with P. g-△NDK, SCC9 and SCC25 cells showed enhanced proliferation, migration, and invasion abilities (P < 0.0001), reduced cytotoxicity (P < 0.0001), and increased extracellular ATP content (P < 0.01). There was a positive correlation between P2X7 expression and extracellular ATP content; in contrast, adding a P2X7 inhibitor produced opposite results (all P < 0.05).In SCC 9 and SCC 25 cells, P. g-△NDK reduces the hydrolysis of extracellular ATP by P. g, which enhances P2X7 expression and results in improved cellular proliferation, migration, and invasion capabilities, along with decreased cytotoxicity.Copyright © 2025 Elsevier Ltd. All rights reserved.