ArticleFrontiers in immunology2026
Non-invasive radiogenomic mapping of the SMARCAL1-driven ferroptotic niche is associated with longitudinal MRD-negative surveillance in early-stage NSCLC.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05457049 (Dynamic Observational Strategy for Stage IB-IIIA Non-Small Cell Lung Cancer Patients After Complete Resection Based on Longitudinal Undetectable Molecular Residual Disease), which is not on this map. Not yet cited in PubMed.
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Dynamic Observational Strategy for Stage IB-IIIA Non-Small Cell Lung Cancer Patients After Complete Resection Based on Longitudinal Undetectable Molecular Residual Disease: Prospective, Multicenter, Single-Arm Study
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9 authors.
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Abstract
Background: 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. Methods: In this single-center translational cohort nested within the prospective CTONG 2201 trial (NCT05457049), 71 patients with completely resected stage IB-IIIA 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 Results: Nine stability-validated radiomic features (selection frequency Π ≥ 0.60, all; ≥ 0.80 for 7/9) constituted the Rad-Score. High Rad-Score patients had longer MFS (HR = 0.32, 95% CI 0.18-0.58; Conclusions: 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. Clinical trial registration: ClinicalTrials.gov, identifier NCT05457049.
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