The role of retrotransposons at the interface of DNA damage and the innate immune response

LINE-1 (L1) retrotransposons are increasingly recognized as key players in cancer biology. While traditionally viewed as mutators through their endonuclease (EN) activity, recent findings show that L1 elements can also activate innate immune pathways independently of EN activity, particularly type I interferon signaling via "viral mimicry." These dual functions position L1 at the intersection of genome regulation and innate immune response. From this perspective, this mini-review discusses recent and still debated insights into L1's role in cancer, including non-cell-autonomous effects mediated by extracellular vesicles, its role in promoting cellular plasticity, and therapeutic opportunities through reverse transcriptase inhibition. Together, these findings highlight L1 retrotransposons as drivers of tumor development and potential clinical targets.