Abstract
Alzheimer's disease (AD) and cancer are immune-mediated disorders characterized by chronic neuroinflammation and immune evasion, respectively. Recent studies implicate two key immune regulators in both diseases: LAG-3, an adaptive immune checkpoint receptor, and TREM2, an innate receptor expressed on microglia and tumor-associated macrophages (TAMs). LAG-3 inhibitors have demonstrated clinical efficacy in cancer and are being explored in AD research. TREM2 activation supports microglial function in AD, while its inhibition may counteract immunosuppressive macrophages in cancer. In this review we compare the roles, mechanisms, and therapeutic strategies targeting LAG-3 and TREM2 in both diseases. We highlight their distinct immune compartmentalization and the importance of context-specific modulation. Strategies include LAG-3 blockade in cancer and AD, and TREM2 agonism or antagonism depending on disease context. We discuss a framework integrating immune compartment, disease state, and therapeutic modality to guide cross-domain immunotherapy development in cancer and AD.