{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T07:02:50Z","timestamp":1779692570258,"version":"3.53.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"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>Post-operative molecular residual disease (MRD) detection using circulating tumor DNA (ctDNA) has been established as a sensitive biomarker for early recurrence risk stratification in early-stage non-small cell lung cancer (NSCLC). However, the biological heterogeneity of patients MRD-negative at baseline remains incompletely characterized, and a proportion subsequently experience MRD conversion and radiographic recurrence. We investigated whether pre-operative radiomic features could non-invasively capture the spatial organization of a ferroptosis-enriched, immune-active tumor microenvironment associated with sustained post-operative MRD negativity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this single-center translational cohort nested within the prospective CTONG 2201 trial (NCT05457049), 71 patients with completely resected stage IB\u2013IIIA NSCLC, MRD-negative at two post-operative landmarks, were followed under dynamic observation without immediate adjuvant therapy. A Rad-Score was derived from 1,432 pre-operative contrast-enhanced CT radiomic features using a pre-specified five-layer pipeline. Whole-exome sequencing, bulk RNA-seq with CIBERSORTx, and 10x Visium spatial transcriptomics in 14 tumors (five High, four Intermediate, five Low Rad-Score; 36,318 quality-controlled spatial spots) characterized molecular correlates. Multiplex immunofluorescence (n = 40 across Rad-Score quartiles), immunohistochemistry (n = 60), CRISPR-Cas9 knockout of SMARCAL1 with wild-type and helicase-dead rescue in A549\/H1299 cell lines, and primary human CXCR3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell chemotaxis assays provided protein-level and functional validation. External validation was performed in two independent cohorts (TCIA NSCLC-Radiogenomics, n = 178; Lung3, n = 89) with locked-model application, following Harrell optimism-corrected internal validation (B\u00a0=\u00a01,000 bootstrap replicates with full-pipeline resampling).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nine stability-validated radiomic features (selection frequency \u03a0 \u2265 0.60, all; \u2265 0.80 for 7\/9) constituted the Rad-Score. High Rad-Score patients had longer MFS (HR\u00a0=\u00a00.32, 95% CI 0.18\u20130.58;\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.001), with apparent C-index 0.812 attenuating to optimism-corrected 0.798 and externally validated 0.783 (NSCLC-Radiogenomics) and 0.741 (Lung3). The Rad-Score remained independent after adjustment for 13 clinical covariates including ECOG PS, Charlson Comorbidity Index, and smoking pack-years (adjusted HR\u00a0=\u00a00.66,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.022), outperformed five established comparators (CALGB 9761-type, Kratz 14-gene, ctDNA composite, Bindea immunoscore, clinical+TMB) in decision curve analysis across the clinically meaningful threshold range 0.15-0.75. High Rad-Score tumors exhibited elevated TMB (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt;\u00a00.001, BH-FDR q &amp;lt; 0.001) and APOBEC signatures (SBS2, SBS13: q &amp;lt; 0.001; SBS4 non-significant after FDR), enriched CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and M1 macrophages (q &amp;lt; 0.01), and contiguous ferroptotic niches with monotonically increasing activity across the Rad-Score continuum (Spearman \u03c1 = 0.87). SMARCAL1 knockout conferred resistance to erastin-induced ferroptosis (cell viability 78 \u00b1 6% in sgSMARCAL1 cells versus 31 \u00b1 4% in sgScramble controls,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.001) and IFN-\u03b3\u2013induced CXCL9\/10 secretion (62%\/57% reduction) \u2014 phenotypes rescued by wild-type but not helicase-dead SMARCAL1 \u2014 and functionally attenuated CXCR3\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell transmigration (58% reduction), with CXCR3 antagonist AMG 487 producing &amp;gt;90% blockade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In this externally validated, functionally interrogated translational cohort, a pre-operative CT-derived Rad-Score is associated with sustained MRD-negative surveillance, provides a non-invasive surrogate for a SMARCAL1-driven ferroptotic-immune niche, and requires prospective validation Non-small cell lung cancer; Molecular residual disease; Radiogenomics; Spatial transcriptomics; Ferroptosis; SMARCAL1; CXCL9\/10-CXCR3 axis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:related-object>\n                      <jats:ext-link>ClinicalTrials.gov<\/jats:ext-link>\n                      , identifier NCT05457049.\n                    <\/jats:related-object>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1835413","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:05:34Z","timestamp":1779689134000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Non-invasive radiogenomic mapping of the SMARCAL1-driven ferroptotic niche is associated with longitudinal MRD-negative surveillance in early-stage NSCLC"],"prefix":"10.3389","volume":"17","author":[{"given":"Zehao","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University","place":["Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JunDao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University","place":["Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University","place":["Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZhanYu","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University","place":["Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajian","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University","place":["Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University","place":["Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HuaFu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University","place":["Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JianJi","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University","place":["Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuo","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, the First Affiliated Hospital of Guangxi Medical University","place":["Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.jtho.2015.09.009","article-title":"The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung 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