Clinicopathological characteristics of tertiary lymphoid structures and development of a preoperative predictive nomogram in resectable non-small cell lung cancer: a multicenter retrospective study

Tertiary lymphoid structures (TLSs) are critical components of the tumor immune microenvironment, yet their prognostic value and clinical assessment in non-small cell lung cancer (NSCLC) across different therapeutic contexts remain inadequately defined. This study aimed to evaluate the impact of TLSs on the prognosis of resectable NSCLC and to develop a preoperative clinical-radiologic nomogram to predict TLSs status. A total of 376 NSCLC patients from Tianjin Chest Hospital were retrospectively enrolled as the training cohort, categorized into a treatment-naive group ( n = 220) and a neoadjuvant chemoimmunotherapy group ( n = 156). An external validation cohort of 224 patients was collected from Fujian Provincial Hospital. TLSs status and maturation were assessed on H&E and immunohistochemical sections. Multivariable Cox and logistic regression analyses were employed to identify independent prognostic factors and clinical-radiologic predictors of TLSs. Predictive nomograms were constructed and evaluated using AUC, calibration curves, and decision curve analysis (DCA). TLSs presence was identified as an independent protective prognostic factor for disease-free survival (DFS) in both treatment-naive and neoadjuvant cohorts (treatment-naive TLSs count: HR 0.332, 95% CI 0.183–0.604; neoadjuvant TLSs status: HR 0.244, 95% CI 0.128–0.465; all P < 0.001). Neoadjuvant chemoimmunotherapy significantly increased TLSs prevalence compared to chemotherapy alone (OR = 4.801, P < 0.001). In the treatment-naive group, high consolidation-to-tumor ratio (CTR), lobulation, pleural traction, and the vacuole sign were independent predictors of TLSs negativity. The training nomogram achieved an AUC of 0.804, with consistent performance in the external validation cohort (AUC = 0.744). For the neoadjuvant group, the nomogram incorporating histological subtype, treatment regimen, and radiologic signs yielded an AUC of 0.739. Calibration and DCA confirmed the robust predictive accuracy and clinical utility of both models. TLSs status is an independent prognostic factor for survival in resectable NSCLC. The developed nomograms provide a non-invasive and objective tool for preoperative TLSs prediction, facilitating personalized therapeutic decision-making and multidisciplinary management for NSCLC patients. Given the retrospective design, these findings warrant prospective, multicenter validation before routine clinical application.