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

Cayleigh Wallace; Alex Gileles-Hillel; Amelia Cox; David Gozal; Wei Li; Hong Yue

Abstract: OPEN ACCESS EDITED BY Xin Li, University of Michigan, United States REVIEWED BY Ramesh Kumar Paidi, Rush University, United States Chenxiao Wang, Tulane University, United States yueh@marshall.edu *CORRESPONDENCE Hong Yue Wei Li [liwe@marshall.edu](mailto:liwe@marshall.edu) † These authors have contributed equally to this work RECEIVED 28 January 2026 REVISED 05 March 2026 ACCEPTED 16 March 2026 PUBLISHED 31 March 2026 CITATION Wallace C, Gileles-Hillel A, Cox A, Gozal D, Li W and Yue H (2026) Thymidine phosphorylase promotes SARS-CoV-2 spike protein-driven lung tumor development. Front. Immunol. 17:1798566. doi: 10.3389/fimmu.2026.1798566 COPYRIGHT © 2026 Wallace, Gileles-Hillel, Cox, Gozal, Li and Yue. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. [Thymidine phosphorylase promotes SARS-CoV-2 spike protein-driven lung tumor development](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1798566/full) Cayleigh Wallace 1 † , Alex Gileles-Hillel 2 † , Amelia Cox 1 , David Gozal 1,3 , Wei Li 1 * and Hong Yue 1 * 1 Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, United States, 2 Pediatric Pulmonology & Sleep, Department of Pediatrics, Hadassah Medical Center, and Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 3 Department of Pediatrics, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV, United States Background: COVID-19 survivors exhibit increased interstitial lung fi brosis, 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: A TriNetX retrospective cohort analysis was combined with mechanistic studies in K18-hACE2 TG and K18-hACE2 TG / Tymp -/ -mice. Mice received intratracheal SP or control lysate followed by a urethane-induced lung cancer protocol. Lung injury, in fl ammation, thrombosis, fi brosis, STAT3 activation, cytokine pro fi les, and tumor burden were assessed. In vitro assays evaluated SP- and RBD-induced ACE2 processing. Results: Propensity score-matched TriNetX cohorts demonstrated an increased lung cancer risk after COVID-19, particularly among current smokers (n = 166,807; RR 1.22; HR 1.50; P<.001). In mice, SP induced acute lung injury, neutrophil in fi ltration, and microthrombi, which were reduced in TYMP-de fi cient mice. SP markedly increased lung tumor incidence and aggressiveness, whereas TYMP de fi ciency reduced tumor formation from 50% to 18% of lung lobes. SP-induced STAT3 upregulation and collagen deposition were signi fi cantly attenuated in K18hACE2 TG / Tymp -/ -mice. Cytokine pro fi ling revealed a tumor-promoting, myeloiddominant in fl ammatory milieu in K18-hACE2 TG mice, in contrast to a T cellin fl amed, anti-tumor pro fi le in K18-hACE2 TG / Tymp -/ -mice. SP and RBD altered ACE2 processing, generating lower-molecular-weight fragments consistent with enhanced turnover. Conclusions: SARS-CoV-2 SP drives lung injury, fi brosis, and..

DOI record: { "DOI": "10.3389/fimmu.2026.1798566", "ISSN": [ "1664-3224" ], "URL": "http://dx.doi.org/10.3389/fimmu.2026.1798566", "abstract": "\n Background\n 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.\n \n \n Methods\n \n A TriNetX retrospective cohort analysis was combined with mechanistic studies in K18-hACE2\n TG\n and K18-hACE2\n TG\n /\n \n Tymp\n –/–\n \n mice. Mice received intratracheal SP or control lysate followed by a urethane-induced lung cancer protocol. Lung injury, inflammation, thrombosis, fibrosis, STAT3 activation, cytokine profiles, and tumor burden were assessed.\n In vitro\n assays evaluated SP- and RBD-induced ACE2 processing.\n \n \n \n Results\n \n Propensity score-matched TriNetX cohorts demonstrated an increased lung cancer risk after COVID-19, particularly among current smokers (n = 166,807; RR 1.22; HR 1.50; P&lt;.001). In mice, SP induced acute lung injury, neutrophil infiltration, and microthrombi, which were reduced in TYMP-deficient mice. SP markedly increased lung tumor incidence and aggressiveness, whereas TYMP deficiency reduced tumor formation from 50% to 18% of lung lobes. SP-induced STAT3 upregulation and collagen deposition were significantly attenuated in K18-hACE2\n TG\n /\n \n Tymp\n –/–\n \n mice. Cytokine profiling revealed a tumor-promoting, myeloid-dominant inflammatory milieu in K18-hACE2\n TG\n mice, in contrast to a T cell-inflamed, anti-tumor profile in K18-hACE2\n TG\n /\n \n Tymp\n –/–\n \n mice. SP and RBD altered ACE2 processing, generating lower-molecular-weight fragments consistent with enhanced turnover.\n \n \n \n Conclusions\n 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.\n ", "alternative-id": [ "10.3389/fimmu.2026.1798566" ], "article-number": "1798566", "author": [ { "affiliation": [ { "name": "Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University", "place": [ "Huntington, WV, United States" ] } ], "family": "Wallace", "given": "Cayleigh", "sequence": "first" }, { "affiliation": [ { "name": "Pediatric Pulmonology & Sleep, Department of Pediatrics, Hadassah Medical Center, and Faculty of Medicine, The Hebrew University", "place": [ "Jerusalem, Israel" ] } ], "family": "Gileles-Hillel", "given": "Alex", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University", "place": [ "Huntington, WV, United States" ] } ], "family": "Cox", "given": "Amelia", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University", "place": [ "Huntington, WV, United States" ] }, { "name": "Department of Pediatrics, Joan C. Edwards School of Medicine at Marshall University", "place": [ "Huntington, WV, United States" ] } ], "family": "Gozal", "given": "David", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University", "place": [ "Huntington, WV, United States" ] } ], "family": "Li", "given": "Wei", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University", "place": [ "Huntington, WV, United States" ] } ], "family": "Yue", "given": "Hong", "sequence": "additional" } ], "container-title": "Frontiers in Immunology", "container-title-short": "Front. 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