Issues

Aggarwal et al. identify two distinct exhausted LAG3⁺CD8⁺ T cell subpopulations in tumors using a lineage-tracing model. One subset acts as a long-lasting progenitor population that maintains anti-tumor immunity and memory, supporting therapeutic strategies targeting LAG3⁺ exhausted T cells to improve tumor control.

Tregs engineered with an orthogonal IL-2 tethered to its receptor persisted without exogenous IL-2 and exhibited superior therapeutic efficacy in a mouse model of type 1 diabetes.

Berzosa et al. identify SorLA as a key regulator of B cell receptor trafficking, which binds immunoglobulin and controls endosomal sorting. Loss of SorLA impairs antigen degradation and reduces antigen-specific responses in vivo, revealing how intracellular trafficking pathways can fine-tune humoral immunity.

Dysregulated immune responses rather than damage by Borrelia burgdorferi alone induce Lyme disease, but mechanisms of disease are poorly understood. Sachan et al. demonstrate that infected mice rapidly develop gut leakiness, endotoxemia, reduced microbiota-reactive antibodies, and systemic markers of inflammatory, some also seen in human Lyme disease patients.

In this work, we identify a new type I IFN–dependent psoriasis subtype resulting from rare heterozygous variants in ADAR1 and associated with a specific response to JAK1 and TYK2 inhibitors, opening new avenues in precision medicine in psoriatic disease.

Cipolla et al. show that antibody can modulate immune responses via both Fc gamma receptor–dependent and –independent mechanisms. These mechanisms influence both the magnitude and composition of the germinal center response.

Koo et al. demonstrate that Plasmodium falciparum circumsporozoite major repeat epitope immunodominance inhibits other highly protective epitopes; current vaccines present this major repeat epitope. The authors show that adding peptide immunogens overcomes this immunogenic gap and enhances protection in vivo.

This study reveals that PML::RARA drives acute promyelocytic leukemia by bridging the PML-bound SUMO machinery and RARA-bound corepressors, enhancing corepressor sumoylation, target gene repression, and the differentiation block. Sumoylation inhibition reactivates downstream targets, triggers myeloid maturation, and blunts progenitor self-renewal.

Evans et al. identify CD1d as a key regulator of myeloid cell diversity in breast cancer. CD1d targeting reshapes tumor immune infiltrates, suppresses tumor growth, and enhances immunotherapy efficacy, suggesting an actionable pathway for therapeutic intervention.

Preventing organ damage is critical for improving outcomes during invasive infections, including invasive candidiasis. Choi et al. demonstrated that tissue-type plasminogen activator protects against kidney damage, thereby highlighting a previously unrecognized tissue-protective signaling pathway that mitigates organ damage during candidiasis.

Therapeutic blocking antibodies against TL1A are emerging as one of the most compelling targets in 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.

IL-17 is well-recognized for orchestrating mucosal antifungal immunity. In this issue of JEM, Choi et al. identify a downstream tPA–LRP1 axis that safeguards the renal epithelium during systemic candidiasis, revealing a mechanism by which IL-17 preserves organ integrity.

Xie, Tebak, et al. propose that persistent implant stress erodes lineage-defining regulatory programs that preserve cell fate and state, uncoupling cellular compensation from tissue needs and driving regulatory drift, thereby reframing implant failure as a loss of adaptive tissue coordination rather than inflammation alone.