Pan-Cancer Analysis Reveals Mutation-Driven TE Dysregulation as a Contributor to Immune Suppression [CUT&Tag]

Somatic mutations and transposable element (TE) dysregulation are hallmarks of cancer, yet how specific genetic alterations influence TE activity across tumor types remains unclear. Here, we mapped mutation–TE regulatory networks across 9,622 tumors representing 33 TCGA cancer types by integrating RNA-seq, whole-exome, and DNA methylation data. Comparative analysis of tumors with and without mutations identified 275 significant cancer–gene pairs associated with altered TE expression, many of which are transcription factors such as TP53, NSD1 and ARID1A. The changes in TE expression were also inversely correlated with DNA methylation changes in many cases. Unexpectedly, we observed that immune pathway activity is down-regulated when TE expression is induced, and up-regulated when TE is repressed. Functional validation in isogenic ARID1A- and CTNNB1-perturbed models recapitulated the changes in TE activity and immune responses observed in TCGA datasets. Together, these findings reveal mutation-driven TE activity reprogramming as a widespread feature and a potential source for immune modulation in human cancers.