The cytokine interleukin‐31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), allergic rhinitis, and airway hyper‐reactivity. In AD, IL‐31 has been identified as one of the main “drivers” of its cardinal symptom, pruritus. Here, we summarize the mechanisms by which IL‐31 modulates inflammatory and allergic diseases. T_H2 cells play a central role in AD and release high levels of T_H2‐associated cytokines including IL‐31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch, and neuronal outgrowth through activation of the heterodimeric receptor IL‐31 receptor A (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes and various innate immune cells. IL‐31 is a critical cytokine involved in neuroimmune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti‐IL‐31 antibody. Accordingly, inhibition of IL‐31‐downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo. However, as to whether downstream JAK inhibitors directly block IL‐31‐mediated‐signaling needs to be clarified. Targeting the IL‐31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory, and pruritic disorders in the future.

Clinically relevant immunological biomarkers that discriminate between diverse hypofunctional states of tumor-associated CD8 ⁺ T cells remain disputed. Using multiomics analysis of CD8 ⁺ T cell features across multiple patient cohorts and tumor types, we identified tumor niche–dependent exhausted and other types of hypofunctional CD8 ⁺ T cell states. CD8 ⁺ T cells in “supportive” niches, like melanoma or lung cancer, exhibited features of tumor reactivity–driven exhaustion (CD8 ⁺ T _EX ). These included a proficient effector memory phenotype, an expanded T cell receptor (TCR) repertoire linked to effector exhaustion signaling, and a cancer-relevant T cell–activating immunopeptidome composed of largely shared cancer antigens or neoantigens. In contrast, “nonsupportive” niches, like glioblastoma, were enriched for features of hypofunctionality distinct from canonical exhaustion. This included immature or insufficiently activated T cell states, high wound healing signatures, nonexpanded TCR repertoires linked to anti-inflammatory signaling, high T cell–recognizable self-epitopes, and an antiproliferative state linked to stress or prodeath responses. In situ spatial mapping of glioblastoma highlighted the prevalence of dysfunctional CD4 ⁺ :CD8 ⁺ T cell interactions, whereas ex vivo single-cell secretome mapping of glioblastoma CD8 ⁺ T cells confirmed negligible effector functionality and a promyeloid, wound healing–like chemokine profile. Within immuno-oncology clinical trials, anti–programmed cell death protein 1 (PD-1) immunotherapy facilitated glioblastoma’s tolerogenic disparities, whereas dendritic cell (DC) vaccines partly corrected them. Accordingly, recipients of a DC vaccine for glioblastoma had high effector memory CD8 ⁺ T cells and evidence of antigen-specific immunity. Collectively, we provide an atlas for assessing different CD8 ⁺ T cell hypofunctional states in immunogenic versus nonimmunogenic cancers.

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within nibrin (NBN), a DNA damage repair protein. Hallmarks of NBS include chromosomal instability and clinical manifestations such as growth retardation, immunodeficiency, and progressive microcephaly. We employed induced pluripotent stem cell-derived cerebral organoids from two NBS patients to study the etiology of microcephaly. We show that NBS organoids carrying the homozygous 657del5 NBN mutation are significantly smaller with disrupted cyto-architecture. The organoids exhibit premature differentiation, and Neuronatin (NNAT) over-expression. Furthermore, pathways related to DNA damage response and cell cycle are differentially regulated compared to controls. After exposure to bleomycin, NBS organoids undergo delayed p53-mediated DNA damage response and aberrant trans-synaptic signaling, which ultimately leads to neuronal apoptosis. Our data provide insights into how mutations within NBN alters neurogenesis in NBS patients, thus providing a proof of concept that cerebral organoids are a valuable tool for studying DNA damage-related disorders.

Despite multimodal therapies, the treatment of glioblastoma remains challenging. In addition to the very complex mechanisms of cancer cells, including specialized phenotypes that enable them to proliferate, invade tissues, and evade immunosurveillance, they exhibit a pronounced resistance to chemo- and radiotherapy. More advanced tumors create a hypoxic environment that supports their proliferation and survival, while robust angiogenesis ensures a constant supply of nutrients. In GBM, these structures are very pronounced and contribute to the creation and maintenance of a highly immunosuppressive microenvironment that promotes tumor growth and immune escape. In addition, the high accumulation of immunosuppressive tumor-infiltrating leukocytes and other cells, the pronounced expression of immune checkpoint molecules, and the low mutational burden, i.e., the low number of neoantigens, are hallmarks of GBM and contribute to the challenge of therapeutic approaches. Here, we review a number of mechanisms that GBM exploits to support tumor growth and potential treatments. These include new chemotherapeutics, tumor treating fields, and small molecules, including compounds targeting angiogenesis or blockers of tyrosine kinases that inhibit tumor cell proliferation and survival. In addition, we focus on immunotherapies such as immune checkpoint blockade or cell therapies, in particular vaccination with dendritic cells and CAR-T cells, which can either kill GBM cells directly or bypass immunosuppression by modulating the tumor microenvironment or boosting the patient’s own immune response.