Issues

Wetternwald and colleagues show that endothelial cells actively regulate energy storage in white adipose tissue through MYCT1–IFITM2/3-dependent control of endolysosomal trafficking and mTORC1 signaling. By limiting their own nutrient consumption, endothelial cells influence systemic energy partitioning, redefining the vasculature as a metabolic gatekeeper rather than a passive conduit.

In this issue of JEM, Forster et al. report that Blimp-1 is a pivotal alarmin-activated transcription factor that is critical in controlling optimal effector cytokine secretion in ILC2 cells during type 2 immunity.

Macrophages are profoundly shaped by their tissue of residence. In this issue, Jayaraman et al. show that TGF-β signaling is crucial for maintaining the identity, function, and spatial organization of long-lived intestinal macrophages, highlighting an essential component of the gut niche.

Song et al. identify Mettl8 as a regulator of progenitor exhausted CD8⁺ T cells, stabilizing Tcf7 transcripts and shaping chromatin programs. Mettl8 loss drives effector differentiation and improves tumor control, underscoring RNA methylation as a key layer of T cell fate regulation.

In this issue of JEM, Tachó-Piñot et al. show that mutated IgD⁺ B cell subsets populate epithelial areas of nasopharyngeal mucosa, ready to tackle a multitude of antigenic targets.

CAFs are prominent members of the TME. Kuhn et al. demonstrate how local gene editing of CAFs alters their cell state and, subsequently, the cellular TME. This approach demonstrates a method to investigate intercellular circuits using targeted genetic perturbations in CAFs.

Hypoxia-inducible factors 1 and 2 (HIF-1/2) play critical roles in cancer progression. We have developed the first dual HIF-1/2 inhibitors that bind to the most highly conserved domains of both proteins, show activity against a wide range of cancers, are orally bioavailable, and markedly improve responses to immune checkpoint blockade in mouse tumor models.

The study reveals that Mettl8 maintains stem-like T_PEX cells by stabilizing Tcf1 via m³C modification and facilitating chromatin looping at the Tox locus. Its deletion or inhibition drives T_PEX differentiation into effective Int-T_EX cells, restraining tumor growth and synergizing with anti–PD-1 therapy, thus presenting a promising immunotherapeutic target.

Mathew et al. demonstrate that CD4 TRM form in the nasal tissue during influenza A virus infection. Influenza-specific CD4 TRM are predominantly Th17, depend on local antigen and CXCR6–CXCL16 axis for formation and maintenance, and are protective upon reinfection.

CDN are second messengers that trigger type I IFN responses. Vila et al. show that DNA-PKcs, a major DNA damage response actor, directly interacts with CDNs through its kinase domain, ensuring CDN-associated signal termination, while CDNs inhibit DNA-PKcs catalytic activity.

Jayaraman et al. challenge the prevailing paradigm that long-lived gut macrophages are restricted to the muscularis, identifying their presence in the lamina propria and using CD163 to distinguish these functionally distinct populations. Deletion of TGF-β signalling molecules demonstrates distinct sub-tissular dependencies of gut macrophages on TGF-β and that macrophages themselves are the key TGF-β–producing population.

During latent pulmonary cryptococcal infection, Zheng et al. show that T_H2-driven STAT6 signaling in monocyte-derived myeloid cells suppresses extracellular fungal clearance, revealing a spatially organized immune checkpoint that promotes pathogen persistence within granulomas.

Forster et al. identify the transcriptional network controlling effector functions of ILC2s downstream of the IL-33 receptor. They found that the Blimp-1–IRF4 axis regulates IL-5 and IL-13 production in ILC2s, driving either worm expulsion or eosinophilia during allergic lung inflammation.

The resolution of inflammation is essential for homeostasis and becomes defective with age. Here, Bex et al. show that basophils infiltrate wounds to promote the resolution and healing in both adult and aged mice.

IgD responses involve a heterogeneous population of IgD class-switched memory B cells that inhabit epithelial areas of the aerodigestive mucosa and differentiate into IgD-secreting plasma cells via a mutation-intensive program targeting the respiratory microbiota and environmental antigens, including airborne allergens.

Wetterwald, Köck et al. report the existence of an endothelial metabolic checkpoint where MYCT1 restricts activity of IFITM2/3 to prevent energy waste at the vascular barrier and enable fat storage. This mechanism links endothelial nutrient handling to systemic energy balance, opening new directions for tackling obesity and metabolic disease.

Endothelial cell gain of MEKK3–KLF2/4 signaling confers CCM by increasing PI3K signaling. We show that the TIE2 receptor links MEKK3–KLF2/4 and PI3K signaling during CCM formation, identifying TIE2 inhibition as a potential treatment strategy for CCM disease.