Metabolic-inflammatory index CTI identifies high-risk early-stage natural killer/T-cell lymphoma and informs a novel prognostic model.

BACKGROUND: The prognostic heterogeneity of early-stage natural killer/T-cell lymphoma (NKTCL) remains inadequately defined. This study aimed to investigate the prognostic value and potential biological relevance of the metabolic-inflammatory biomarkers in early-stage NKTCL. METHODS: We conducted a secondary analysis on 166 patients with early-stage NKTCL from a multicenter clinical trial (NCT02631239). C-reactive protein-triglyceride-glucose Index (CTI) was calculated as: 0.412* Ln (CRP [mg/L]) + Ln (TG [mg/dL] × FPG [mg/dL])/2. Cox proportional hazards models and restricted cubic spline analyses were applied to assess the association and dose-response relationship between CTI and overall survival (OS). Mechanistic insights were explored through animal experiments and clinical lymphocyte-subset analyses. Independent prognostic factors were identified using multivariable Cox regression, and a composite prognostic model incorporating CTI, body mass index (BMI), and albumin (ALB) was subsequently developed and internally evaluated. RESULTS: High CTI was independently associated with inferior OS in patients with early-stage NKTCL, with a significant linear dose-response relationship. Patients with high CTI had a higher incidence of B symptoms and elevated lactate dehydrogenase and β2-microglobulin levels. A simplified CTI-BMI-ALB prognostic model demonstrated moderate predictive performance for 1-, 3-, and 5-year OS, with AUCs of 0.71, 0.71, and 0.69, respectively, and an overall C-index of 0.69 (95% CI: 0.59-0.79). In the present cohort, the CTI-BMI-ALB model showed improved discriminative performance compared with conventional prognostic indices and provided additional survival stratification among patients classified as low-risk or favorable-risk by these indices within this cohort. In vivo experiments showed that the Gubra-Amylin NASH diet-induced metabolic-inflammatory state with elevated CTI levels was associated with accelerated lymphoma progression, reduced intratumoral CD8+ T-cell infiltration, and increased proportions of Tregs and M2 macrophages. Consistently, clinical lymphocyte-subset analysis confirmed Treg enrichment in patients with high CTI and a positive association between CTI and the proportion of Tregs. CONCLUSION: CTI is an independent prognostic biomarker in early-stage NKTCL, reflecting systemic metabolic-inflammatory and immune dysregulation. The CTI-BMI-ALB model, which integrates inflammatory, nutritional, and metabolic dimensions, showed potential for complementary risk stratification beyond conventional prognostic indices and warrants further validation before broader clinical application.