Developing a novel necroptosis-related signature to evaluate the prognostic and therapeutic characteristics of esophageal cancer

Background: The prognostic assessment and therapeutic interventions of esophageal cancer (ESCA) require novel molecular targets. The prognostic value of necroptosis, a specific mode of programmed cell death strongly linked to cancer progression, remains largely unexplored in ESCA. The primary goal of this research is to develop a necroptosis-based prognostic signature, which will represent the microenvironmental characteristics and prognosis of individuals diagnosed with ESCA. Methods: Transcriptome data of ESCA samples from The Cancer Genome Atlas were utilized to screen for necroptosis-related long non-coding RNAs (NR-lncRNAs) and genes (NRGs). The research employed the least absolute shrinkage and selection operator (LASSO) regression and univariate Cox regression analysis to identify prognostic candidates. Based on these analyses, a signature was developed in the training set and subsequently verified in the testing and entire sets. A clinicopathologic relevance assessment was carried out, after which a nomogram was established. The features of the immune microenvironment, functional pathways, mutational burden, checkpoint expression, and stemness of tumors were analyzed. Moreover, the sensitivity of individuals to immunotherapy and chemotherapy was compared for therapeutic guidance. Results: A necroptosisassociated signature comprising two genes and eleven lncRNAs was constructed. High-risk patients showed worse prognosis and clinicopathologic features, with more tumor-infiltrating naive B cells, CD4+ memory resting T cells, and regulatory T cells. Furthermore, stromal and ESTIMATE scores were decreased along with increased stemness scores and tumor mutational burden in high-risk individuals. For the quantitative prediction of the outcomes of individuals, a nomogram was established. High-risk individuals showed greater sensitivity to immunotherapy while low-risk individuals benefited more from conventional chemotherapeutic or targeted therapy. Conclusion: A necroptosis-related prognostic signature was developed to study the tumor microenvironment, mutational burden, clinical features, and the treatment response of ESCA patients. This may contribute to precision medicine for ESCA.