Thymidine phosphorylase promotes SARS-CoV-2 spike protein-driven lung tumor development

Background: COVID-19 survivors exhibit increased interstitial lung fibrosis, a known risk factor for lung cancer. We investigated whether SARS-CoV-2 spike protein (SP)-induced lung injury and elevated thymidine phosphorylase (TYMP) promote lung tumorigenesis. Methods: assays evaluated SP- and RBD-induced ACE2 processing. Results: mice. SP and RBD altered ACE2 processing, generating lower-molecular-weight fragments consistent with enhanced turnover. Conclusions: SARS-CoV-2 SP drives lung injury, fibrosis, and tumorigenesis through a TYMP-dependent mechanism involving STAT3 signaling and inflammatory microenvironment remodeling. COVID-19 significantly increases lung cancer risk, especially in current smokers. TYMP represents a potential therapeutic target to mitigate long-term pulmonary consequences of COVID-19.