Characterization of tumour microenvironment in thymic epithelial tumours of different histological subtypes

Thymic epithelial tumours (TETs) include several World Health Organization (WHO) defined histological subtypes, ranging from indolent thymomas to highly aggressive thymic carcinoma (TC). The characteristics of the tumour microenvironment (TME), including immune and metabolic profiles, and their prognostic implications across subtypes remain poorly defined.

We analyzed tissue samples from 111 patients with TET treated at Sun Yat-sen University Cancer Center (SYSUCC) and transcriptome and single nucleotide polymorphism data from 119 patients in The Cancer Genome Atlas (TCGA). Mutation tree analysis was performed to delineate genetic relationships among the six WHO subtypes. Immune cell infiltration was assessed using CIBERSORT, and amino acid, fatty acid, glucose metabolic activities were quantified with gene set variation analysis. Candidate immunometabolic biomarkers for malignant subtypes were validated by immunohistochemistry in the SYSUCC cohort.

The mutation tree demonstrated clear genetic divergence among TET subtypes. TC and type B3 thymomas were the most genetically distinct, in keeping with their higher malignant potential and poorer prognosis, whereas type A and AB thymomas clustered together, consistent with their indolent behavior. TME profiling identified three clusters: type A and type AB, type B1 and type B2, and type B3 and TC. Patients with TC or type B3 thymoma exhibited increased macrophage infiltration, enhanced amino acid and fatty acid metabolism, and reduced resting dendritic cells. Immunohistochemistry confirmed overexpression of CD68, GLS2, and ARG2 in aggressive subtypes.

This integrative analysis highlights evolutionary divergence and TME heterogeneity across TET subtypes and identifies immunometabolic biomarkers that may support prognostic assessment and future personalised treatment stratification in aggressive TETs.