V. Fife, C. P. Bromley, M. Roberts, I. C. H. Lee, D. Grainger, A. Chaturvedi, C. Zhou, C. M. Fife, K. Morris, A. Fuertes Gassio, S. Atkinson, S. Sivagnanam, K. Betre, A. J. Cheeseman, M. Crowther, J. C. M. Wan, T. Karasaki, D. Millrine, E. Kilgour, N. McGranahan, M. Jamal-Hanjani, C. Swanton, TRACERx consortium, L. M. Coussens, P. A. J. Crosbie, C. Dive, S. Zelenay
With increased lung cancer screening, early-stage diagnoses and recurrences are expected to rise. Identifying the ~20% of patients with early-stage non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), who relapse after curative-intent surgery remains a major clinical challenge. Here, we identify a COX-2-associated pro-tumorigenic inflammatory signature (PTI) in resected tumors as an independent predictor of disease relapse in both LUAD and LUSC, with particular utility within one year after surgery in stage I NSCLC. We developed a clinically compatible workflow for PTI scoring in tumor resections and validated its predictive performance in real-world samples from routine care and screening programs. Spatial immune profiling revealed that PTIhigh tumors, which swiftly recur, exhibit markedly reduced tumor cell content alongside expanded neutrophil-rich immune-stromal compartments. These findings link COX-2-driven inflammation to early post-surgical recurrence in NSCLC and indicate that PTI may serve as a biomarker for risk stratification to guide imaging surveillance and adjuvant therapy decisions.