Our study established (1) the effects of the tumor suppressor TSPX on the EGFR signaling oncogenic pathway, among others, in lung adenocarcinoma pathogenesis and clinical outcomes and (2) highlighted TSPX as a potential marker for differential diagnosis and prognosis of the two subtypes, lung adenocarcinoma and squamous cell carcinoma, of NSCLC. This evidence concerns the gene TSPYL2 and squamous cell carcinoma.