Issues

Terez Shea-Donohue is the program director of the Division of Digestive Diseases and Nutrition at the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. As a program director, Terez supports basic and translational research related to neurogastroenterology, gastrointestinal (GI), and GI epithelial barrier function.

In this issue of JEM, Robles-Oteiza et al. present compelling evidence linking tumor hypoxia to acquired resistance mechanisms in non-small cell lung cancer (NSCLC) treatments involving immune checkpoint inhibitors (ICIs). Their research advocates targeting these hypoxic tumor regions with hypoxia-activated pro-drugs like TH-302, which may substantially delay the onset of resistance and herald a significant advancement in cancer therapy.

Chan et al. and Ru et al., identify defective RNA processing as the root cause of impaired antiviral immunity against SARS-CoV2 in the human brainstem and provide molecular insight into virus-associated severe brainstem encephalitis through PKR inactivation.

Our understanding of MAIT cell biology is increasing rapidly. Here, Germain et al. discuss recent findings regarding MAIT cell functions in barrier tissues, with a focus on the role of pathogen- and microbiota-derived MAIT cell ligands.

Cirigliano and Fine explore the past, present, and future of glioma modeling, identifying limitations in current models and proposing new approaches integrating bioengineering and artificial intelligence. These innovations aim to better capture tumor heterogeneity and human brain microenvironment, enhancing therapeutic relevance and clinical translatability.

This article explains how germline genetic factors and environmental exposures shape clonal hematopoiesis, the accumulation of somatic variants within hematopoietic tissues during one’s lifespan, which confers risk for solid and hematopoietic malignancies as well as cardiovascular and numerous inflammatory diseases.

Pretreatment gut microbiomes of immunotherapy-related colitis patients drive worse colitis in susceptible mice compared with non-colitis cancer immunotherapy microbiomes. Microbiome shifts in immunotherapy-related colitis initially mirror inflammatory bowel disease patients but subsequently resolve suggesting a reversible, colitogenic state.

Specifically depleting CD206-expressing TAMs using a novel mouse model demonstrates the role of these macrophages in recruiting a tumor-reactive network of CD8 T cells, cDC1s, and NK cells.

Understanding mechanisms driving tumor escape during immune checkpoint inhibition is essential to combat acquired resistance. This study identifies hypoxia as a key feature of immune checkpoint inhibitor-resistant tumors and demonstrates that therapeutically targeting tumor hypoxia can delay acquired resistance.

The accumulation of RNA lariats in human DBR1-deficient cells impairs stress granule assembly–mediated PKR activation, and thereby cell-intrinsic antiviral immunity. Cells and brain samples from Dbr1^Y17H/Y17H mice exhibit similar phenotypes. These findings provide a molecular mechanism by which human-inherited DBR1 deficiency underlies brainstem viral infections.

Dominant negative variants in ITPR3, encoding a subunit of the IP₃ receptor, cause Ca²⁺ channel leakiness resulting in ER store depletion and impaired T cell Ca²⁺ dynamics. Patients present with incompletely penetrant syndromic combined immunodeficiency, ectodermal dysplasia, and multisystem disease.

This study reveals an underlying mechanism that mediates the rapid release of cytokines by ILC3s. Upon stimulation, the p38α–eIF6–Nsun2 axis rapidly promotes the nuclear export of cytokine mRNA in ILC3s, thereby maintaining intestinal homeostasis.

The microbial metabolite succinate promotes tuft cell hyperplasia, which enhances the gut’s ability to protect against intestinal infections. This study reveals that microbiome-driven tuft cells’ hyperplasia in the colon helps defend against Clostridioides difficile infection, providing a pathway through which host and microbial interactions protect against pathogens. Succinate-producing bacteria improve survival in infected mice, and this protective effect is dependent on the presence of tuft cells, as evidenced by the lack of protection in tuft cells–deficient mice.

Metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma is particularly resistant toward immunotherapies. Through a multipronged approach integrating databases consisting of over 1,000 HCC patients and multiple murine HCC models, we identified SiglecF^hi TANs-derived TGFβ as the key driver of their immune evasion and ICB therapy resistance.

STAG2 is a frequently mutated cohesin subunit across several cancers and one of the most important functional suppressors of lung adenocarcinoma. Our findings underscore important roles of STAG2 in suppressing lung tumorigenesis and highlight a STAG2-PAXIP1/PAGR1 tumor-suppressive program that may transcend cancer type.

JNK1 is a novel drug target in CLL, downstream of the proximal B cell receptor kinases BTK, SYK, and PI3K. JNK1 inhibitors effectively block CLL progression in TCL-tg mice and in human patient-derived CLL xenograft models, overcome microenvironmental protection, restore T cell functions, and even inhibit ibrutinib-resistant CLL.