The role of inhibitory receptors in immune homeostasis and disease: emerging mechanisms and therapeutic advances

Inhibitory receptors have increasingly been recognized as critical players in the maintenance of immune homeostasis. These receptors, expressed on a variety of immune cells such as T cells, B cells, NK cells, myeloid, and innate lymphoid cells, function as checkpoints by delivering suppressive signals through domains such as immunoreceptor tyrosine-based inhibitory motifs (ITIMs). They are essential in preventing overactive immune responses, maintaining tolerance, and protecting tissues from immune-mediated damage. However, disruption of their signaling contributes to a spectrum of pathologies, including chronic inflammation, autoimmune disorders, immune exhaustion, and ineffective pathogen clearance. Although recent advances have highlighted their potential in treating cancer and chronic infections, where inhibitors such as PD-1 and CTLA-4 show success, there remains much to learn, particularly about their function in non-lymphoid and non-immune cells such as epithelial and endothelial cells.

This Research Topic aims to further our understanding of inhibitory receptors by addressing key questions about their varied roles across cellular contexts, their regulation during different physiological and pathological states, their interaction with co-stimulatory pathways, and their understudied roles in non-immune cells. Our goals are to showcase new discoveries, elucidate underlying mechanisms, and foster therapeutic advancements using multidisciplinary methodologies that integrate molecular immunology, systems biology, and translational science.

To gather further insights into the dynamic and multifaceted roles of inhibitory receptors, we welcome articles addressing, but not limited to, the following themes:

• Homeostatic functions of inhibitory receptors in both immune and non-immune cells
• Molecular mechanisms regulating their expression and signaling
• Tissue-specific expression and context-dependent regulation
• Crosstalk among inhibitory pathways and their integration with co-stimulatory signaling
• Roles in immune dysfunction associated with infection, cancer, autoimmunity, and chronic inflammation
• Therapeutic targeting of inhibitory receptors using biologics or small molecules, including identification of novel checkpoint molecules
• Technological advances in profiling inhibitory receptors (e.g., single-cell omics, spatial transcriptomics, imaging)

We encourage interdisciplinary submissions that merge mechanistic inquiry with translational insight. Manuscripts exploring lesser-characterized inhibitory pathways or their roles in non-immune cells are particularly encouraged. Please note that purely clinical studies without mechanistic analyses will not be considered.

We welcome original research articles, reviews, brief reports, and perspectives.