Reawakening retrotransposons: immune modulation in normal and malignant hematopoiesis

Retrotransposons are mobile repetitive elements that constitute around 43% of the human genome. Normally silenced through epigenetic mechanisms, retrotransposons can become reactivated in response to various stimuli, producing immunogenic DNA, RNA, and peptides that trigger innate and adaptive immune responses. In normal hematopoiesis, retrotransposon reactivation can drive inflammatory signaling responses, which support stem cell activity, influencing hematopoietic stem and progenitor cell (HSPC) regeneration. In hematological cancers, their reactivation can alter the tumor microenvironment and promote immune evasion. Here, we highlight the complex interactions between retrotransposons, hematopoiesis, and immune modulation. We also emphasize the therapeutic potential of targeting retrotransposons, while addressing critical knowledge gaps in retrotransposon-driven immune modulation across both health and disease.