Immune checkpoint (IC) pathways, originally identified in T-cell exhaustion in cancer, are increasingly recognized as key modulators of immune tolerance in autoimmune diseases (ADs). In ADs, these molecules function more accurately as inhibitory receptors (IRs) that fine-tune, rather than inducing classical exhaustion phenotypes, autoreactive immune cells. Unlike oncology, where checkpoint blockade enhances immunity, AD therapy aims to restore tolerance through IC agonism or immune reset approaches (e.g., CAR-T cells). This review synthesizes recent advances in targeting CTLA-4, PD-1, LAG-3, TIM-3, and TIGIT. Clinical success with CTLA-4-Ig (abatacept) and emerging efficacy of PD-1 agonists (e.g., peresolimab) provide proof-of-concept that augmenting inhibitory signaling can ameliorate autoimmunity. However, outcomes remain context-dependent, reflecting interplay between effector and regulatory subsets and tissue-specific environments. Mechanistic challenges, including multivalent receptor engagement, ligand complexity, and signaling heterogeneity (e.g., ITIM/ITSM phosphorylation), limit current approaches. Insights from immune-related adverse events (irAEs) highlight shared pathways of dysregulation and inform risk-benefit considerations. A major translational gap persists between acute transplant models and chronic autoimmunity, and validated predictive biomarkers are lacking. Beyond T cells, B cells, dendritic cells, and innate populations expand therapeutic opportunities. Future progress will require multi-omics profiling, biomarker-driven stratification, and next-generation agonist design. IC-targeted strategies hold promises but demand context-aware, mechanistically informed development for broad clinical impact in ADs.

Sjögren's disease (SjD) is a systemic autoimmune disorder primarily affecting exocrine glands alongside heterogeneous organ involvement. Historically managed through symptomatic relief and conventional disease-modifying therapies, recent immunological advances have steadily expanded our understanding of its pathogenesis and therapeutic approaches.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following hematopoietic stem cell transplant, with the skin being one of the most common and persistently affected organs in acute and chronic forms of the disease. Topical corticosteroids and supportive dermatologic care are foundational in mild cutaneous disease; however, moderate-to-severe disease frequently requires systemic corticosteroid therapy. Despite systemic corticosteroids being first-line therapy in moderate-to-severe disease, up to 60% of patients will develop steroid-refractory or steroid-resistant disease, emphasizing the need for alternative therapies. Recent advances in GVHD management have led to the introduction of targeted systemic agents, such as ruxolitinib, belumosudil, axatilimab, ibrutinib, and abatacept, each addressing different pathways implicated in disease pathogenesis and leading to incorporation into disease management based on established algorithms or select clinical contexts. Additionally, local immunomodulatory therapies, such as topical ruxolitinib, phototherapies, and extracorporeal photopheresis, can be utilized as adjunctive therapies for persistent or localized cutaneous disease. Cellular therapies, specifically mesenchymal stromal cells and regulatory T cells (Treg), are emerging therapies with promising potential in modulating the immune response and improving clinical outcomes. This review summarizes the current standards of care and recent therapeutic advances in the management of cutaneous GVHD, focusing on evidence-based therapies and skin-specific outcomes.

T cell receptor (TCR) engagement stimulates formation of a biomolecular condensate, including the scaffold protein linker of activated T cells (LAT). We investigated whether the immune-inhibitory receptor programmed cell death protein 1 (PD-1) inhibits by impeding TCR-induced LAT condensation. In vitro reconstitutions revealed that the cytoplasmic domain of PD-1 directly inhibited LAT condensation. This inhibitory interaction required tyrosine residues in the two inhibitory motifs of PD-1. Contrary to current working models, tyrosine phosphorylation eliminated PD-1 inhibition. Replacing tyrosine with tryptophan reconstituted PD-1 inhibition in T cells, confirming that phosphorylation does not mediate this effect. These findings support the concept that hydrogen bond-donating aromatic residues within inhibitory motifs provide the primary mechanism that explains how inhibitory receptors disrupt signaling networks and block immune activation.

Immune checkpoint inhibitor (ICI)-associated myocarditis is uncommon but has been described as an important and potentially fatal complication of cancer treatment. Increasing evidence from a variety of data sources have reframed this complication as part of ICI-associated myotoxicity (ICI-M), a systemic cardiomuscular syndrome in which myocarditis, myositis, conduction disease, ventricular arrhythmias, dysphagia, pseudo-myasthenic oculobulbar signs, and respiratory muscle failure may coexist. Elevated troponin with ICI use is not synonymous with myocarditis but instead should trigger a structured evaluation that considers symptoms, ECG findings, troponin and creatine kinase concentrations, structural and functional assessments including left ventricular function, pathology when feasible, and exclusion of alternative causes including other cardiotoxic therapies. The severity of ICI-M is heterogeneous and can now be stratified using the presence of active thymoma, cardiomuscular symptoms, low QRS-voltage, left ventricular ejection fraction <50%, and magnitude of troponin elevation. Low-risk cases such as patients with abnormal cardiac biomarkers only may be monitored closely, whereas severe ICI-M requires monitored admission, early respiratory and swallowing assessment, ICI interruption, and rapid multidisciplinary immunosuppression. Corticosteroids are generally recommended; however, severe, progressive, or refractory disease increasingly supports pathophysiology-directed-based therapies, including abatacept and ruxolitinib. Abatacept inhibits CD80/CD86-CD28 co-stimulation and can be titrated to CD86 receptor occupancy of the monocytes. Ruxolitinib inhibits Janus kinase/signal transducer and activator of transcription cytokine signaling pathway and may complement abatacept bioactivity. Evidence is promising for these therapies but not definitive, pending prospective trials. Rechallenge is often avoided but could be reassessed in selected patients under strict surveillance.

Triple M overlap syndrome is a rare, but often fatal, immune-related adverse event. Evidence on the effectiveness of immunosuppressive treatments, including abatacept, and disease monitoring in complex cases remains limited.