As people age, their immune systems gradually lose the ability to control inflammation and fight cancer effectively. In solid tumors, this age-related immune decline often tips the balance toward immunosuppression, allowing cancers to grow unchecked. Two major shifts drive this problem: an overproduction of immature myeloid cells that suppress immune responses and the loss of tissue-resident macrophages, which normally repair damage and restore immune balance. Why this breakdown happens with age remains poorly understood. At the same time, aging cells experience widespread genomic instability, including the reactivation of transposable elements, which are DNA sequences that can trigger inflammatory alarm signals. How transposable elements contribute to immune dysfunction, chronic inflammation, and cancer progression in older individuals is a major unanswered question and addressing it could reveal entirely new ways to restore immune homeostasis and improve cancer outcomes in aging populations.
This project will investigate how age-dependent reactivation of transposable elements, particularly LINE-1 (L1), reshapes the myeloid immune landscape to promote tumor-supportive inflammation. Using advanced single-cell genomic and epigenomic profiling, the research will map L1 expression and sensing pathways across myeloid progenitors and tissue-resident macrophages in young and aged mice. Complementary genetic and pharmacologic approaches, such as L1-deficient mouse models and reverse transcriptase inhibitors, will be used to test whether dampening L1 activity can restore immune homeostasis, reduce pathological myelopoiesis, and restrain tumor growth. These mechanistic studies will be integrated with preclinical cancer models to assess therapeutic potential. By linking epigenetic dysregulation to immune aging this work will establish L1 as a novel target for repurposing existing drugs and inform new strategies to counteract inflammaging and enhance cancer immunotherapy in older patients.