Innate lymphoid cells: Bridging basic biology and disease

Innate lymphoid cells (ILCs) lack antigen-specific receptors and are, consequently, distinct from conventional T and B lymphocytes. Nevertheless, they play a critical role in immune regulation through the rapid secretion of effector cytokines. Due to these functional properties, ILCs exhibit remarkable similarities to CD4⁺ T helper lymphocytes. With the inclusion of natural killer (NK) cells in the current ILC classification, ILCs are now considered the innate immune system counterparts of adaptive T lymphocytes. Recent studies have demonstrated that ILCs are essential for maintaining tissue homeostasis, particularly at mucosal surfaces, and their dysregulation is closely linked to the pathogenesis of inflammatory, autoimmune and allergic diseases. Beyond their roles in chronic inflammation, ILCs act as pivotal integrators of dietary, microbial, and neuroendocrine signals within specialized tissue microenvironments. In allergic diseases and asthma, ILC2s initiate early type 2 responses, while in the intestinal mucosa, plasticity between ILC3 and ILC1 subsets critically regulates the balance between homeostasis and inflammatory bowel disease (IBD). Additionally, ILCs are emerging as significant players in tumor immunology, exhibiting both pro- and anti-tumorigenic roles depending on the tumor microenvironment. This review provides a comprehensive overview of ILC biology, their tissue-specific functions, and their involvement in immune-mediated disorders. Moreover, we discuss the therapeutic potential of targeting ILCs, including cell-based approaches and their significance as biomarkers, to establish a framework for next-generation precision immunotherapies.