Innate lymphoid cells (ILCs) fulfill critical roles in maintenance of tissue-specific homeostasis but have also been implicated in disease pathology when dysregulated. Although they are broadly classified into three core subsets, it is increasingly apparent that ILCs exhibit plasticity in response to microenvironmental factors. Accurate and holistic evaluation of the ILC landscape is critical to understanding the contribution of ILCs to disease pathology. Using high-parameter flow cytometry, we comprehensively interrogated the phenotypic and functional diversity of ILCs in healthy volunteers and patients with severe asthma (SA), assessing the reciprocity between peripheral blood and airway compartments and dissecting the impact of anti–IL-5/5Rα biologics on these responses. We identified substantial heterogeneity and putative plasticity in human ILC responses, highlighting inherent limitations of conventional enumeration strategies. Deep phenotypic and functional profiling demonstrated a distinct sexual dimorphism in ILC responses in patients with SA. Females displayed an elevated abundance of circulating ILC progenitors, ILC1s, and ILC3s, whereas males presented with diminished ILC2s compared with respective healthy controls. Circulating ILC progenitors inversely correlated with testosterone concentrations. Moreover, we identified a reciprocal influx of all core ILC subsets into the airways of patients with SA, with unbiased multisource clustering identifying a relationship between elevated airway ILC2s and reduced lung function. Last, we showed that anti–IL-5/5Rα biologics largely ablated airway ILC type 2 cytokine production without affecting core ILC subset abundance in the peripheral blood or airways, identifying a potential mechanism whereby anti–IL-5/5Rα biologics alleviate clinical disease in patients with SA.

Multiple myeloma (MM) is a genetically and clinically heterogeneous plasma cell malignancy characterised by clonal expansion of differentiated B cells within the bone marrow (BM). Patients start with monoclonal gammopathy of undetermined significance (MGUS) and progress to an intermediate stage called smouldering multiple myeloma (SMM), characterised by several genetic alterations that represent the genomic backbone of the malignant clone. Immune checkpoint pathways play a central role in shaping an immunosuppressive BM niche, contributing to T-cell dysfunction, immune evasion, and therapeutic resistance. Key inhibitory receptors such as PD-1, CTLA-4, TIM-3, LAG-3, and CD47 are frequently dysregulated, promoting T-cell exhaustion, anergy, and senescence. Emerging evidence highlights extracellular vesicles (EVs) as critical mediators of intercellular communication in MM. MM-derived EVs carry bioactive cargo, including proteins and miRNAs, that reprogram immune and stromal cells, enhancing tumour progression and immune escape. Notably, EV-associated immune checkpoint molecules contribute to the establishment of a permissive microenvironment. This review provides an integrated overview of immune checkpoint dysregulation and EV-mediated immunomodulation in MM, emphasising their role in disease pathogenesis and progression. Furthermore, we discuss the therapeutic potential of targeting immune checkpoints and exploiting EVs as novel biomarkers and drug delivery systems, highlighting their promise for improving precision medicine approaches in MM.