Issues

Long-term maintenance of immune memory is critical for the control of recurring virus infections and cancer. In this issue of JEM, Ma et al. report that the E2 ubiquitin–conjugating enzyme UBE2F restrains long-term CD8 T cell memory.

Mínguez-Martínez et al. identify a cooperative RBPJ-STAT5-SMAD4-RXRα-PPARγ transcriptional network that integrates DLL4, GM-CSF, and TGFβ signals to establish alveolar macrophage identity. Their findings position endothelial DLL4 as early licensing signal that enables recruited monocytes to acquire tissue-resident macrophage fate.

In this Viewpoint, Paludan and Cherry reflect on the recent hantavirus outbreak and discuss need of a better understanding of the different phases of viral diseases to improve treatment.

Ward et al. review how conventional type 1 dendritic cells (cDC1s) coordinate antitumor immunity through cross-presentation, immune cell networking, and spatial organization in tumors. They discuss recent advances linking cDC1 state and location to immunotherapy response, and outline strategies to expand or reprogram cDC1s to improve the durability of cancer immunotherapies.

Physical cues such as tissue stiffness, stretch, and flow shape immune responses across diverse tissues. This review positions mechano-inflammation as a unifying framework linking mechanotransduction to inflammatory signaling in health and disease, highlighting translational opportunities for diagnosis and therapy.

Tissue-resident CSF1R-dependent CD169⁺ macrophages localize deep in the skin. They surround growing tumors and directly suppress their growth independent of T and B cells. CD169⁺ skin macrophages ingest live tumors, and this phagocytosis is independent of the phosphatidylserine receptor MERTK.

Memory B cell longevity underlies protection against reinfection. In this study, Cody et al. show that complement activation regulates memory B cell longevity in mice, shaping repertoire composition by modulating homeostatic proliferation and attrition of this B cell subset.

We developed a highly efficient nonviral knock-in platform for NK cells, enabling plasmid-based genome editing with up to ∼90% knock-in efficiency and ∼100% recovery. Targeted integration rewires endogenous circuits for context-dependent therapeutic functions and supports GMP-compatible production of CAR-NK cells for clinical translation applications.

Abrahimi et al. evaluate intravesical CAR T cell delivery as a therapeutic platform for organ-confined bladder cancers. By targeting MUC16, they demonstrate intravesical administration uncouples antitumor efficacy from systemic engraftment, overcoming a major CAR T cell toxicity barrier in solid tumors.

Although memory and exhausted CD8 T cells arise through distinct differentiation pathways, this study reveals that targeting UBE2F induces a shared resilience program characterized by heightened IL-15 responsiveness and enhanced longevity. This differentiation-independent program improves CD8 T cell durability and immune protection in both viral infection and tumor settings.

Blanco-Domínguez et al. demonstrate that regulatory T cells constrain IFNγ-producing γδ T cells by competing for IL-2, thereby limiting their expansion and anti-tumor function. IL-2Rβγc agonism can overcome this suppression to enhance γδ T cell–mediated tumor control.

CNOT3 promotes the degradation of Tbx21 and Rorc mRNAs through Roquin and ZFP36L1 in ILC2 cells, thereby inhibiting type 1 and type 3 plasticity and maintaining ILC2 function.

Bruand et al. reveal that cathepsin S as a regulator of B cell maturation in germinal center reactions, high-affinity antibody production, and formation of tertiary lymphoid structures. Both its deficiency and hyperactivation disrupt immune balance either weakening anti-tumor responses or fostering lymphomagenesis.

Tissue-resident macrophages acquire distinct identities shaped by local signals. Mínguez-Martínez et al. show that RXRs drive alveolar macrophage differentiation by regulating chromatin and gene expression in cooperation with other regulatory elements. DLL4, GM-CSF, and TGFβ coordinate transcriptional networks that, together with the RXR–PPARγ axis, establish and maintain alveolar macrophage population and identity.

Al Jawazneh, Liebold, Leyk et al. show that engulfment of bile acid–loaded hepatic parenchymal cells results in the transfer of bile acids to phagocytic macrophages, altering their inflammatory profile. This identifies dying cells, and specifically their bile acid content, as active modulators of macrophage function, potentially driving chronic inflammation in cholangiopathies such as primary sclerosing cholangitis.

Roci et al. identify water channel AQP1 as a hallmark of postnatal lymphatic vascular remodeling in hyperosmolar inflammatory microenvironments. AQP1 sustains lymphatic endothelial cell migration under osmotic stress, establishing tissue osmolarity as a key biophysical determinant of postnatal lymphangiogenesis.

Using an unbiased forward mutagenesis screen in an autochthonous mouse model, we have identified new mechanistic determinants of aggressive prostate cancer. SIRT1 emerged as a key regulator of neuroendocrine prostate cancer differentiation and a potential target for therapeutic intervention.