Transposable element splicing reveals a tumor-enriched class of gene-independent transcripts.

Abstract

Transposable elements (TEs) are broadly reactivated in tumors, but their repetitive nature has limited transcript-level characterization. Here, we systematically investigate the TE-derived splicing landscape across pan-cancer samples and define a splice-resolved subset of TE-derived transcripts, termed TEtrans, with tumor enrichment and gene independence. TEtrans initiate within TEs, spliced within or between TE loci, and are composed predominantly of TE sequences. Their expression was associated with stemness and inflammation regulators in a context-dependent manner. Functional analyses identify an endogenous retrovirus-derived TEtrans that promotes colorectal cancer growth by enhancing topoisomerase I-mediated DNA relaxation. A subset of TEtrans encodes shared tumor antigens that elicit antigen-specific cytotoxic T cell responses, while a murine TEtrans-like transcript mediates antigen-dependent tumor control in vivo. Collectively, TEtrans represent a splice-resolved source of TE-derived oncogenic drivers and actionable tumor antigens, broadening the scope of TE reactivation in cancer.