Therapeutic blocking antibodies against TNF-like cytokine 1A (TL1A) are emerging as one of the most compelling targets in inflammatory bowel disease (IBD). Preliminary phase 2 studies using TL1A-blocking antibodies have demonstrated some of the highest response rates seen in UC and CD. As the field waits for definitive phase 3 study results, the first of which are expected this summer, mechanistic data continue to expand the biological scope of TL1A in IBD.

A high-affinity antibody response to both infection and vaccination critically relies on the ability of B cells to capture and process antigen for presentation to CD4+ T cells. The cellular processes from antigen recognition to full B cell activation require a finely orchestrated series of events, involving signalling and intracellular trafficking mechanisms. Here, we describe a novel regulator of B cell receptor (BCR) endocytosis and intracellular trafficking. Multidomain trafficking protein sorting-related receptor with A-type repeats (SorLA) associates with the BCR and regulates uptake of both soluble and substrate-bound antigens. SorLA deletion results in altered BCR-antigen intracellular trafficking to degradative compartments, modulating eventual antigen presentation. Crucially, this change in antigen trafficking results in a significant reduction in plasma cells and humoral responses in vivo. Given the critical importance of antigen presentation in immunity, as well as autoimmune disease and malignancy, these results identify a new cellular pathway in B cell biology with potential implications for immune regulation.

Antibody-drug conjugates (ADCs) have become an increasingly important component of the therapeutic landscape of many solid tumors. Currently, there are eight ADCs approved for solid tumors, with hundreds being developed and in clinical trials. Initially being approved in the advanced or metastatic settings, ADCs are also being incorporated as neoadjuvant or adjuvant therapies. In this review, we discuss the important components of ADC design in the context of clinical successes and failures. We further evaluate mechanisms of intrinsic and acquired resistance and strategies to overcome these barriers. Finally, we discuss the landscape of potential combination partners to increase efficacy of ADC therapies.

There is a higher density of immune cells in peritoneal fluid than is found in blood. Thus, any perturbations, from sterile injury to endometriosis to ovarian cancer, require immune cells to recognize and nucleate to these sites. Using peritoneal injuries as a prototype, we saw a massive recruitment of large peritoneal macrophages (LPMs) interspersed with mast cells. The mast cells were activated by sensory neurons to mobilize their 1-μm granules to the cell surface. Lattice light sheet microscopy unveiled a new step in the mast cell degranulation. After granules fused with the plasma membrane, cytonemes (very thin long filopodia) grabbed the granules from the mast cell surface and deposited them on neighboring LPMs. The granules were membraneless biomolecular condensates and harbored more than 200 different proteins, including MARCO, which mediated rapid LPM aggregation to the injury nidus. The condensates also induced a repair-like phenotype in the macrophages that helped heal the injury site.

Invasive Candida albicans infections (candidiasis) cause progressive organ damage through fungal tissue invasion and toxin-mediated injury, including in the kidney. Hyphal invasion induces apoptosis of renal tubular epithelial cells (RTEC), a key driver of kidney pathology, yet intrinsic renal protective mechanisms remain poorly defined. We identify fibrinolytic tissue-type plasminogen activator (tPA) as a critical mediator of renal tissue protection in candidiasis. tPA is induced by IL-17 and TNFα in renal endothelial cells and RTEC. tPA signals through low-density lipoprotein receptor-related protein 1 (LRP1) and activates ERK1/2 signaling to suppress apoptosis in RTEC. Mice with RTEC-specific deletion of LRP1 exhibited exaggerated kidney damage during candidiasis. Administration of a nonenzymatic form of tPA recapitulated the protective effect of tPA by limiting RTEC apoptosis. These findings reveal the role of tPA/LRP1 axis in preserving renal integrity in candidiasis and suggest clinically approved tPA as a potential therapeutic strategy to mitigate candidiasis-associated tissue injury.

IL-17 is well-recognized for orchestrating mucosal antifungal immunity. In this issue of JEM, Choi et al. (https://doi.org/10.1084/jem.20260530) identify a downstream tPA-LRP1 axis that safeguards the renal epithelium during systemic candidiasis, revealing a mechanism by which IL-17 preserves organ integrity.

Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies. Along with the typical neurologic and rheumatologic manifestations, severe pulmonary disease is increasingly recognized yet poorly understood. We studied three siblings presenting with early-onset, life-threatening pulmonary alveolar proteinosis (PAP) and autoinflammatory stigmata. Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a key mediator of IFN-I signaling, which also facilitates feedback inhibition via USP18. R223Q STAT2 preserved signal transduction and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate IFN-I responses, owing to impaired localization of USP18. Unlike in classical forms of PAP, GM-CSF signaling remained intact. Instead, persistent IFN-I signaling antagonized monocyte migration toward chemokines essential for lung trafficking. Informed by these findings, the youngest sibling received JAK inhibitor and anti-IFN-I receptor therapy with marked clinical improvement. Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP.

Homozygosity for rare loss-of-function IL23R variants abolishes IL-23-dependent IFN-γ production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R, and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with an MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12Rβ1 and bind IL-23. However, their function is impaired by low levels of cell surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-γ production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria.

Recent evidence implicates altered RNA editing and dysregulated type I IFN signaling in immune-mediated diseases, including psoriasis, although the underlying genetic mechanisms remain poorly defined. We investigated four unrelated multiplex families with early-onset plaque psoriasis, with or without psoriatic arthritis, segregating as a monogenic trait and characterized by a strong IFN signature in skin and blood. Whole-exome sequencing identified four rare heterozygous loss-of-function mutations in ADAR1 cosegregating with disease and elevated IFN-stimulated gene expression. Six additional rare variants were detected in an independent cohort of 125 psoriasis patients. Single-cell transcriptomics identified keratinocytes and melanocytes as major IFN sources. Functional studies showed that ADAR1 knockdown or expression of ADAR1G1119R and ADAR1P3A alleles pathogenic variants reduced adenosine-to-inosine RNA editing and increased IFN-stimulated genes and inflammatory cytokines, effects reversed by upadacitinib and deucravacitinib. These findings define a novel IFN-dependent psoriasis subtype caused by inborn defects of ADAR1-mediated RNA editing, with direct implications for precision medicine in psoriatic disease.

CD137 is expressed in a subset of Foxp3+ regulatory CD4 T cells (Tregs), but its immunoregulatory role is not fully defined. Due to alternative splicing that removes the transmembrane domain-encoding exon, CD137 exists in both membrane and soluble forms. We investigated the function of CD137 in Foxp3+ Tregs using the NOD mouse model of type 1 diabetes (T1D). Foxp3+ Treg-specific deletion of CD137 reduced circulating soluble CD137 and accelerated T1D development, driven by heightened clonal expansion and differentiation of effector T cells in pancreatic islets. CD137 deficiency in Foxp3+ Tregs reduced their frequency in islets and impaired their differentiation toward a suppressive phenotype. Restoring soluble CD137 in Foxp3+ Tregs lacking its membrane form reduced islet T cell activation and mitigated T1D acceleration without altering the accumulation of suppressive Foxp3+ Tregs. Our results indicate that both soluble and membrane forms of CD137 expressed by Foxp3+ Tregs are critical for immunoregulation, and they independently restrain T1D development.

The nervous system has emerged as a critical regulator of cancer progression. Recent studies demonstrate that peripheral neurons shape tumor growth, dissemination, and therapeutic response by regulating multiple components of the tumor microenvironment. In parallel, tumors within the body remodel their neural niche by recruiting innervation and modulating neuronal phenotype and activity. This bidirectional cross talk positions neural circuits as integral components of the tumor ecosystem, linking environmental cues, including metabolic stress, inflammation, and the impact of treatment, to coordinated multicellular responses that promote progression and treatment resistance. Here, we review the field of cancer neuroscience with a focus on solid tumors originating outside the central nervous system. We synthesize mechanistic insights into how the peripheral nervous system shapes the tumor microenvironment to influence tumor behavior and highlight emerging therapeutic opportunities to target neural pathways. Together, these findings identify the nervous system as an upstream regulator of cancer biology and a tractable target for intervention.

Type III IFNs, or IFNλ, are pleiotropic immune mediators that mostly work at mucosal surfaces by signaling in epithelial cells and selected immune cells. Zhou, Zhang, and colleagues (https://doi.org/10.1084/jem.20251858) demonstrate that IFNλ also signals in kidney fibroblasts sustaining renal fibrosis.

In this issue of JEM, Schroeder et al. (https://doi.org/10.1084/jem.20251959) report that the transcription factor BACH2 has context-dependent dual functions in regulating the differentiation of follicular T helper cells.