{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T07:03:48Z","timestamp":1774940628716,"version":"3.50.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A TriNetX retrospective cohort analysis was combined with mechanistic studies in K18-hACE2\n                      <jats:sup>TG<\/jats:sup>\n                      and K18-hACE2\n                      <jats:sup>TG<\/jats:sup>\n                      \/\n                      <jats:italic>\n                        Tymp\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\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                      <jats:italic>In vitro<\/jats:italic>\n                      assays evaluated SP- and RBD-induced ACE2 processing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\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&amp;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                      <jats:sup>TG<\/jats:sup>\n                      \/\n                      <jats:italic>\n                        Tymp\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      mice. Cytokine profiling revealed a tumor-promoting, myeloid-dominant inflammatory milieu in K18-hACE2\n                      <jats:sup>TG<\/jats:sup>\n                      mice, in contrast to a T cell-inflamed, anti-tumor profile in K18-hACE2\n                      <jats:sup>TG<\/jats:sup>\n                      \/\n                      <jats:italic>\n                        Tymp\n                        <jats:sup>\u2013\/\u2013<\/jats:sup>\n                      <\/jats:italic>\n                      mice. SP and RBD altered ACE2 processing, generating lower-molecular-weight fragments consistent with enhanced turnover.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1798566","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T05:32:42Z","timestamp":1774935162000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Thymidine phosphorylase promotes SARS-CoV-2 spike protein-driven lung tumor development"],"prefix":"10.3389","volume":"17","author":[{"given":"Cayleigh","family":"Wallace","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Joan C. 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