TNF-α has been confirmed to promote tumor growth in LSCC. PGE2 expression in LSCC tissues was significantly higher than in tumor-adjacent tissues. In the present work, we aimed to discover the combined role of TNF-α and PGE2 in LSCC progression and its potential mechanisms. TNF-α and PGE2 were quantified by ELISA. TRAF2, MMP-9 and GRK2 expressions were detected by immunohistochemistry and western blot. UM-SCC-11A cell proliferation was tested by CCK-8, and cell migration and invasion were determined by transwell assay. GRK2/TRAF2 interaction was tested by Co-IP. The results showed that TNF-α, PGE2, TRAF2, MMP-9 and GRK2 expressions were significantly higher in tumor tissues than in tumor-adjacent tissues. Higher expressions of TRAF2, MMP-9 and GRK2 were associated with poorer prognosis of LSCC. Combined TNF-α with PGE2 promoted UM-SCC-11A cell proliferation, migration and invasion. The interactions of TRAF2 and GRK2, as well as MMP-9 expression, were upregulated in response to TNF-α and PGE2 co-stimulation. In conclusion, we found crosstalk between PGE2 and TNF-α signaling pathways, and the interaction between GRK2 and TRAF2 led to the activation of TNF-α-TRAF2-MMP-9 signaling and resulted in the progression of LSCC.