Ferroptosis regulators related scoring system by Gaussian finite mixture model to predict prognosis and immunotherapy efficacy in nasopharyngeal carcinoma.

The role of ferroptosis in tumor progression and metastasis has been demonstrated. Nonetheless, potential biological function of ferroptosis regulatory pattern in nasopharyngeal carcinoma (NPC) remains unknown. Ferroptosis regulatory patterns of nasopharyngeal carcinoma samples were evaluated based on 113 ferroptosis regulators and three distinct ferroptosis subtypes were determined by unsupervised clustering. The ferroptosis score (FEP score) was identified to quantify ferroptosis patterns within individual tumors by Gaussian finite mixture model and systematically correlated with representative tumor characteristics. Subtype 1 and subtype 3 were consistent with immune activated phenotype, while subtype 2 was consistent with immune suppressed phenotype. High ferroptosis score, characterized by immune activation and suppression of mRNA based stemness index (mRNAsi) and Epstein-Barr virus (EBV) genes, indicated an immune activated tumor microenvironment (TME) phenotype, with better progression free survival (PFS) and lower risk of recurrence and metastasis. Low ferroptosis score, characterized by activation of Wnt and NF-κB signaling pathways and lack of effective immune infiltration, indicated an immune suppressed tumor microenvironment phenotype and poorer survival. High ferroptosis score was also correlated to enhanced response to immunotherapy, and was confirmed to correlate with therapeutic advantages and clinical benefits in an anti-programmed cell death 1 ligand 1 (PD-L1) immunotherapy cohort. As ferroptosis played a crucial role in the tumor microenvironment's diversity, assessing the ferroptosis pattern within individual tumor with ferroptosis score could enhance our understanding of tumor microenvironment infiltration characterization and help develop more effective immunotherapy.

Liu Z ，He J ，Hu X 《Frontiers in Genetics》

m6A Regulators Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization In Nasopharyngeal Carcinoma.

The role of RNA N6-methyladenosine (m6A) modification in tumor progression and metastasis has been demonstrated. Nonetheless, potential biological function of m6A modification patterns in nasopharyngeal carcinoma (NPC) remains unknown. The m6A modification patterns were comprehensively evaluated based on 26 m6A regulators in NPC, and m6A subtype and also m6A score were identified and systematically correlated with representative tumor characteristics. Two distinct m6A subtypes were determined and were highly consistent with immune activated and immune suppressed phenotypes, respectively. More representative m6A scores of individual tumors could predict tumor microenvironment (TME) infiltration, mRNA based stemness index (mRNAsi), EBV gene expression, genetic variation, and prognosis of NPC patients. Low m6A score, characterized by activation of immunity and suppression of mRNAsi and EBV gene, indicated an activated TME phenotype and better PFS and also lower risk of recurrence and metastasis. High m6A score, characterized by activation of Wnt and NF-κB signaling pathway and lack of effective immune infiltration, indicated an immune suppressed TME phenotype and poorer survival. Low m6A score was also correlated with increased tumor mutation burden (TMB) and better response to immunotherapy, and vice versa. A significant therapeutic advantage in patients with low m6A score was confirmed with an anti-PDL1 immunotherapy cohort. m6A patterns played an important role in the diversity and complexity of TME. m6A score could be used to evaluate the m6A pattern of individual tumor to enhance our understanding of TME infiltration and guide more effective immunotherapy strategies.

Liu Z ，He J ，Han J ，Yang J ，Liao W ，Chen N ... -  《Frontiers in Immunology》

Ferroptosis Regulator Modification Patterns and Tumor Microenvironment Immune Infiltration Characterization in Hepatocellular Carcinoma.

Accumulating studies have highlighted the biologic significances of ferroptosis modification in tumor progression, but little is known whether ferroptosis modification patterns have potential roles in tumor microenvironment (TME) immune cell infiltration of hepatocellular carcinoma (HCC). In this study, we evaluated 51 ferroptosis regulators and performed consensus clustering algorithm to determine ferroptosis modification patterns and the ferroptosis related gene signature in HCC. Gene set variation analysis (GSVA) was employed to explore biological molecular variations in distinct ferroptosis modification patterns. Single sample gene set enrichment analysis (ssGSEA) algorithm was performed to quantify the relative infiltration levels of various immune cell subsets. Principal component analysis (PCA) algorithm was used to construct the ferroptosisSig score to quantify ferroptosis modification patterns of individual tumors with immune responses. Three distinct ferroptosis modification patterns were identified. GSVA enrichment analysis indicated that three ferroptosis modification subgroups were enriched in different metabolic pathways. ssGSEA analysis determined that 19 of 24 immune infiltrating cells had significant differences in three distinct ferroptosis patterns. A 91-ferroptosis gene signature was constructed to stratify patients into two ferroptosisSig score groups. Patients in the higher ferroptosisSig score were characterized by significantly prolonged survival time compared with patients in the lower ferroptosisSig score group (p < .0001). An immunotherapy cohort confirmed patients with higher ferroptosisSig score determined significant therapeutic advantages and clinical benefits. Receiver operating characteristic (ROC) curve analysis confirmed the predictive capacity of anti-PD/L1 immunotherapy by ferroptosisSig score. Our study indicated the ferroptosis modification played a significant role in TME heterogeneity and complexity. Evaluating the ferroptosis modification pattern of individual tumor could strengthen our cognition of TME infiltration characteristics and guide more effective clinic immunotherapy strategies.

Liu DL ，Wu MY ，Zhang TN ，Wang CG ... -  《Frontiers in Molecular Biosciences》

Molecular subtypes based on ferroptosis-related genes and tumor microenvironment infiltration characterization in lung adenocarcinoma.

Recently, several molecular subtypes with different prognosis have been found in lung adenocarcinoma (LUAD). However, the characteristics of the ferroptosis molecular subtypes and the associated tumor microenvironment (TME) cell infiltration have not been fully studied in LUAD. Using 1160 lung adenocarcinoma samples, we explored the molecular subtypes mediated by ferroptosis-related genes, along with the associated TME cell infiltration. The ferroptosis score was constructed using the least absolute shrinkage and selection operator regression (LASSO) method to quantify the ferroptosis characteristics of a single tumor. Three different molecular subtypes related to ferroptosis, with different prognoses, were identified in LUAD. Analysis of TME cell infiltration revealed immune heterogeneity among the three subtypes. Cluster A was characterized by immunosuppression and was associated with stromal activation. Cluster C was characterized by a large number of immune cells infiltrating the TME, promoting tumor immune response, and it was significantly enriched in immune activation-related signaling pathways. Relatively less infiltration of immune cells was a feature of cluster B. The ferroptosis score can predict tumor subtype, immunity and prognosis. A low ferroptosis score was characterized by immune activation and good prognosis, as seen in the cluster C subtype. Relative immunosuppression and poor prognosis were the characteristics of a high ferroptosis score, as seen in cluster A and B subtypes. At the same time, the anti-PD-1/L1 immunotherapy cohort demonstrated that a low ferroptosis score was associated with higher efficacy of immunotherapy. The ferroptosis score is a promising biomarker that could be of great significance to determine the prognosis, molecular subtypes, TME cell infiltration characteristics and immunotherapy effects in patients with LUAD.

Zhang W ，Yao S ，Huang H ，Zhou H ，Zhou H ，Wei Q ，Bian T ，Sun H ，Li X ，Zhang J ，Liu Y ... -  《OncoImmunology》

The Ferroptosis Molecular Subtype Reveals Characteristics of the Tumor Microenvironment, Immunotherapeutic Response, and Prognosis in Gastric Cancer.

Xu X ，Zhou N ，Lan H ，Yang F ，Dong B ，Zhang X ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》