Comprehensive analysis of cuproptosis-related lncRNAs in immunotherapy response and prognosis in papillary thyroid cancer

Background: Cuproptosis is a copper-induced mechanism of programmed cell death (PCD) that may influence the progression of papillary thyroid cancer (PTC). However, research linking this route to long non-coding RNAs (lncRNAs) in PTC is limited. This study assesses the correlation between cuproptosis-associated lncRNAs and immunotherapy sensitivity as well as clinical outcomes in PTC.

Methods: PTC transcriptomic profiles, tumor mutational burden (TMB), and clinical annotations were obtained from The Cancer Genome Atlas (TCGA). Cuproptosis-associated lncRNAs were identified via co-expression analysis with known cuproptosis genes. We employed least absolute shrinkage and selection operator (LASSO)-penalized Cox modeling to develop a lncRNA signature for predicting progression-free survival (PFS) and calculated a patient-level risk index. Subsequently, we evaluated the associations among this index, immune infiltration, predicted immunotherapy response, and clinical outcomes.

Results: Ten lncRNAs associated with cuproptosis-related risk were identified. Using the median value of risk score, we stratified individuals into higher- and lower-risk strata. Individuals in the higher-risk category exhibited poorer PFS, disease-specific survival (DSS), and overall survival (OS) rates. In multivariable Cox models, the lncRNA-derived score independently predicted PFS and outperformed traditional clinicopathologic factors as demonstrated by receiver operating characteristic (ROC) and C-index comparisons. A nomogram that incorporates the risk score alongside essential covariates exhibited well-calibrated estimates for PFS at 1, 3, and 5 years. The heightened risk was positively correlated with increased immune-cell infiltration, augmented immunological effector actions, and elevated expression of immune checkpoints. Model-based inference indicated that high-risk patients are more likely to get benefits from immune-checkpoint blocking, with enhanced results expected from anti-programmed cell death protein 1 (PD-1) or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy. The reverse transcription quantitative polymerase chain reaction (RT-qPCR) results demonstrated that LINC01545 overexpressed in PTC tissues while DLG3-AS1 downregulated in PTC tissues compared with the normal tissues, which is in consistent with the bioinformatic results.

Conclusions: A lncRNA signature associated with cuproptosis serves as an independent predictor of clinical outcomes and immunotherapy response in PTC, supporting the use of these transcripts as biomarkers for risk stratification and treatment selection guidance.