Emergency granulopoiesis and innate immune memory in inflammatory bowel disease

Emerging evidence now points to innate tissue immunity as a critical orchestrator of both local tissue adaptation and long-range hematopoietic reprogramming, including the amplification of emergency granulopoiesis through bone marrow progenitor remodeling. These findings position the intestine as an instructive niche capable of imprinting long-lived changes both locally and systemically. This review synthesizes current findings at the intersection of gut and bone marrow biology, examining how intestinal inflammation shapes granulopoietic output and how bone marrow-derived effectors, in turn, reinforce maladaptive tissue responses that underlie chronic intestinal manifestations, including colitis-associated cancer and extraintestinal inflammatory complications frequently seen in IBD. We delineate the physiological framework governing these regulatory nodes and highlight the translational implications for next-generation therapeutic intervention.

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SenSpots: when B cells age in place

Spatial multi-omics of aging human lymph nodes by Fan and colleagues reveals that immunosenescence manifests as focal B cell coalescence into ‘SenSpots’ within germinal centers, where concerted epigenetic, transcriptional, proteomic, and metabolic reprogramming spatially orchestrates the decline of humoral immunity.

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Parental leave in immunology - 10

My research focuses on the fundamental biology of MAIT cells, a population of metabolite-sensing unconventional T cells. I investigate their roles in host defence and allergy, I also define MR1-presented antigens and the way they are recognised, with the aim of harnessing or inhibiting their function therapeutically.

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Targeting the fate of exhausted CD8+ T cells

CD8+ T cell exhaustion is increasingly recognized as a regulated adaptation to chronic antigenic stimulation rather than a simple immune failure. Indeed, recent studies reveal that exhaustion is imprinted early after T cell activation, integrating transcriptional and epigenetic cues to balance effector function with long-term persistence. Key regulators, including Inhibitor of DNA binding 3 (ID3), Thymocyte selection high mobility box protein (TOX), MYB, Krüppel-like factor 2 (KLF2), and Special AT-rich sequencing binding protein 1 (SATB1), orchestrate this process, preserving stem-like precursor populations that sustain immunity during chronic infection and cancer. This emerging view frames exhaustion as a context-dependent extension of the memory program rather than its collapse. By defining the molecular and functional logic of exhaustion, we highlight how these insights can inform new approaches to manipulate T cell fate for therapeutic benefit.

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A macrophage compass for pigeons

Homing pigeons’ navigation in darkness relies on Earth’s magnetic field. However, the underlying mechanism of magnetoreception remains poorly understood. Recently, Lisowski et al. demonstrated that superparamagnetic hepatic macrophages are potential magnetoreceptors that detect and transmit geomagnetic information to support the navigation of pigeons.

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Parental leave in immunology - 9

I am a cancer biologist with a strong interest in B-cell biology, lymphoma evolution, and autoimmunity. I had my daughter in 2024 while completing my postdoctoral research in Professor Andrejs Braun’s laboratory at Barts Cancer Institute, Queen Mary University of London. Although I was entitled to up to 1 year of maternity leave, I chose to take 7 months. What initially felt like a pause in my career became a meaningful period of reflection on my scientific direction, priorities, and long-term goals.

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Functional heterogeneity of macrophages in distinct niches of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies, characterized by a highly complex and dynamic tumor microenvironment in which tumor-associated macrophages (TAMs) are particularly abundant. TAMs regulate tumor initiation, progression, metastasis, and therapy response, making them attractive targets. However, targeting TAMs remains challenging due to their remarkable plasticity and functional heterogeneity. Recent high-throughput multi-omics studies have revealed that the HCC microenvironment consists of distinct regions defined by cellular architecture, such as the fibrotic invasive margin, perivascular niche, poorly vascularized hypoxic/necrotic areas, and cancer stem cell niche, each associated with unique protumorigenic properties. This review summarizes TAM heterogeneity across liver niches, disease stages, and treatment contexts, and evaluates TAM-targeted strategies, emphasizing key unresolved challenges to improving HCC outcomes.

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Antigen uptake: Breaking convention

More than 4 decades after the discovery of MHC restriction, it is clear that the phagocytosis of dying cells is not the only route by which macrophages acquire antigens. Fan and colleagues further expand this paradigm by showing that macrophages can sample a living cell’s cytosol and bypass classical endolysosomal processing.

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Biomaterial-guided macrophage modulation: Therapeutic engineering of immune microenvironments

Macrophages are central regulators of immunity, tissue homeostasis, and repair, whose plasticity enables them to integrate cues from their local microenvironment. Dysregulated macrophages contribute to chronic inflammation, fibrosis, impaired wound healing, and tumor progression. Biomaterials enable the modulation of macrophages through localized delivery of immunomodulatory signals and by creating instructive microenvironments. In this review, we examine macrophage–biomaterial interactions, emphasizing how surface chemistry, topography, mechanics, porosity, and degradation profiles shape macrophage recruitment and phenotype. We discuss emerging strategies for macrophage modulation, including programmable systems that provide spatiotemporal control over immune signaling. We further highlight how these applications can improve disease outcomes. Finally, we discuss design considerations, characterization, and translational challenges that must be overcome to advance macrophage-targeted biomaterials toward clinical implementation.

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Adenosine as a metabolic checkpoint in CD8+ T cell dysfunction

CD8+ T cell dysfunction, characterized by impaired effector function, proliferative capacity, and sustained inhibitory receptor expression, limits immune control in both cancer and chronic viral infections. Despite arising from distinct disease processes, these conditions induce a shared state of CD8+ T cell dysfunction, suggesting convergence on common regulatory pathways. Adenosine (ADO), an immunosuppressive purine metabolite generated through extracellular ATP catabolism, has emerged as a context-integrating metabolic checkpoint that regulates immune responses in response to tissue stress and inflammation. Across tumors and HIV, dysregulated ADO signaling reinforces checkpoint pathways and stabilizes dysfunctional CD8+ T cell states. In this review, we examine how the ADO–adenosine deaminase-1 axis shapes CD8+ T cell dysfunction across disease contexts and discuss its potential as a broadly applicable target for immune restoration.

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IL-33 scripts cancer immunity

Interleukin-33 (IL-33) is classically viewed as an alarmin, but in cancer, it may do more than merely initiate immunity. I propose that IL-33 scripts the trajectory of immunity through interconnected regulatory layers that influence how host responses are organized and ultimately resolved into either productive antitumor immunity or suppressive, repair-like states.

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Mitochondrial Ca2+ signaling: A metabolic rheostat defining tumor and immune cell fate

Mitochondrial calcium (mtCa2+) has long been framed as a bioenergetic regulator, yet evidence redefines it as a relevant immunometabolic switch. Within the tumor microenvironment, the mitochondrial calcium uniporter (MCU) complex and the NCLX–TMEM65 efflux axis maintain a ‘Goldilocks zone’ of Ca2+ homeostasis. This can be exploited by cancer cells to sustain oxidative phosphorylation and tricarboxylic acid-derived oncometabolite production, including succinate, fumarate, and 2-hydroxyglutarate, while imposing ionic and nutrient constraints on infiltrating immune cells. Chronic mtCa2+ overload in effector T cells drives mitochondrial dysfunction and exhaustion, while oxidative phosphorylation-dependent Ca2+ flux enforces the acquisition of an immunosuppressive profile in macrophages. Disrupting these tumor–immune ionic imbalances through selective MCU modulation or efflux pathway targeting offers a strategy to restore immune surveillance and/or enhance immune checkpoint inhibitor therapies.

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Cross-priming underlies the efficacy of antibody–drug conjugates and immunotherapy combinations

Antibody–drug conjugates (ADCs) selectively deliver potent chemotherapeutic agents to tumor cells. In clinical settings, the therapeutic benefits of ADCs can be improved when combined with immune checkpoint inhibitors, probably due to the immunogenic nature of ADC-induced tumor cell death, which releases tumor antigens to be cross-presented by conventional type-1 dendritic cells (cDC1). This opinion article proposes that cDC1-mediated cross-presentation and cross-priming represent a central, still poorly understood, and underexploited immunological mechanism that links ADC-induced tumor cell death to durable antitumor immunity. Such mechanisms open opportunities for combinations with established and experimental immunomodulatory agents. Aside from checkpoint inhibitors, synergy has also been observed with agonist monoclonal antibodies directed to costimulatory receptors, increasing the potency of the ensuing antitumor immune response.

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Gut microbiome metabolites meet immunometabolism in inflammatory bowel disease

Growing evidence indicates that gut microbiota-derived metabolites are key regulators of immunometabolism in inflammatory bowel disease (IBD). Intestinal epithelial cells and immune cells exhibit profound metabolic alterations in IBD. Microbial metabolites act as intermediates in host–microbe communication, reshaping mitochondrial functions and cellular metabolic pathways, thereby impacting immune functions. Dysbiosis may, therefore, perturb immune homeostasis by rewiring host metabolic circuits. Understanding how microbial metabolites orchestrate immunometabolic crosstalk in the gut and leveraging it to recalibrate host immunometabolic circuits represents promising, underexplored therapeutic avenues. In this review, we highlight emerging concepts on how gut microbiota-derived metabolites shape immune cell immunometabolism and discuss the therapeutic potential of targeting the microbiota–metabolite–immunometabolism axis in IBD.

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Metabolic regulatory nodes of the inflammasome and inflammatory cell death

Inflammation is a metabolically intensive and tightly regulated process, driven primarily by innate immune cells. Cellular metabolism actively instructs immune signaling and cell fate decisions. Bioenergetic pathways, including glycolysis, mitochondrial respiration, and the tricarboxylic acid cycle, reshape cytokine production and regulate inflammatory cell death pathways. In this review, we synthesize emerging evidence on how metabolic intermediates and pathways regulate inflammasome signaling and the execution of diverse inflammatory cell death modalities, including pyroptosis, necroptosis, PANoptosis, and ferroptosis. We propose that metabolic inputs—including redox balance, mitochondrial dynamics, and lipid modifications—constitute an interconnected metabolic regulatory network that determines the threshold and outcome of inflammatory signaling. This framework offers new insights into immunometabolic dysregulation and therapeutic strategies in inflammatory, infectious, and neoplastic diseases.

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Parental leave in immunology — 6

I am a biologist with training in Genetics and Molecular and Cellular Biology, but my path has always been guided by a deep interest in immunology and in understanding how life experiences shape our biology. During my PhD, including a period at Harvard Medical School (McLean Hospital), I began investigating how stress—especially early-life stress—modulates immune function and influences vulnerability to mood disorders. I later continued this line of research as a postdoctoral researcher at Pontifical Catholic University of Rio Grande do Sul (PUCRS), Brazil.

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T cell control of the intestinal barrier and gut microbiota during ageing

The epithelial, microbial, and immune components of the intestinal barrier coexist in harmony to prevent undesirable inflammatory outcomes and ensure homeostasis in the host. In this review, we outline molecular mechanisms by which T cells regulate intestinal homeostasis and how the ageing-associated dysfunction of T cells could disturb host–microbiota symbiosis and the physical integrity of the intestinal barrier, ultimately driving inflammageing and poor health outcomes. Finally, we propose microbiota- and T cell-based therapeutic interventions aimed at strengthening the intestinal barrier to promote healthier longevity. Namely, we discuss the transplantation of youthful microbiota, the use of designed probiotics, and the adoptive transfer of competent or engineered T cells.

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Context-dependent androgen control of T cell immunity

While androgen deprivation is widely used in urological oncology to restrain tumor growth and prevent T cell exhaustion, Lee et al. reveal a striking reversal in glioblastoma. In glioblastoma, androgen loss triggers microglial cytokines, activates the hypothalamic–pituitary–adrenal axis, and induces glucocorticoid-dependent T cell suppression, which accelerates tumor progression.

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Parental leave in immunology — 8

Katharina Schmack

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Parental leave in immunology — 5

I am an immunologist with over 15 years of experience in translational biomedical research, specializing in T cell biology, autoimmune diseases, and gastrointestinal cancers. My work explores how immune cells maintain balance, drive inflammation, and regulate epithelial transformation, with a growing focus on immune–microbiome interactions and strategies to therapeutically modulate them. I also earned an Executive MBA to support this translational vision. Beyond research, I am committed to advancing women’s participation in science, promoting gender-responsive medicine in inflammatory bowel disease and colon cancer, and fostering connections between patient associations and key stakeholders.

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Parental leave in immunology — 7

I am a cancer immunologist and a junior group leader in precision immuno-oncology in Milan, Italy. My work focuses on developing personalized immunotherapy strategies for solid tumors, generating patient-specific tumor-reactive T cells, and investigating how tumors escape immune surveillance. In November 2022, while I was a postdoctoral researcher in Italy, I took parental leave following the birth of my child.

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Bioelectric signaling as an emerging layer of macrophage communication

Bioelectric signaling may represent an emerging layer of macrophage communication. This forum discusses how membrane-potential dynamics, ion fluxes, and context-dependent intercellular coupling may coordinate macrophage responses within tissues, highlighting a potential new dimension of immune regulation with broad implications for tissue-level immunity.

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DNA sensing and regulation of lipid metabolism

Immunity and metabolism are deeply intertwined in maintaining homeostasis. With the recognition of cytosolic dsDNA sensing as an initiator of immune responses, its interface with metabolic rewiring has emerged as a key area of investigation. Focusing on the stimulator of interferon genes adaptor protein, critical for dsDNA-mediated inflammation, we examine the link between lipid metabolism and innate immunity. Adopting an evolutionary perspective and through comparisons with the inflammasome pathway, also specialized in innate immune activation, we explore the conservation of this interface across innate immune systems. We propose that the connection between dsDNA sensing and metabolism could unlock innovative precision medicine strategies for inflammatory diseases.

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A pancreatic intraepithelial neoplasia—Oramic view of early pancreatic cancer in 3D

Pancreatic cancer is a deadly disease defined by an immunosuppressive microenvironment refractory to therapy. Kiemen et al. applied 3D histology, imaging mass cytometry, and spatially resolved DNA sequencing to human pancreata containing early precursors of the disease, revealing heterogeneous and mutation-specific inflammatory niches that are poorly resolved by 2D methods.

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Promoting intestinal regeneration without tumor risk in immune-mediated inflammatory diseases

Immune-mediated inflammatory disorders, such as inflammatory bowel diseases, are characterized by chronic inflammation and damage to the intestinal barrier. Several of the current therapeutic strategies for inflammatory diseases attempt to decrease inflammation but cause side effects in a significant fraction of patients without promoting remission. Leveraging the power of intestinal regeneration for therapeutic purposes holds great promise, but it comes with the significant risk of promoting tumorigenesis, as most of the pathways that boost the regenerative program are also exploited by tumor cells for their growth and survival. In this article, we review the common mechanisms promoting intestinal regeneration and tumor development and discuss the latest studies identifying cellular and molecular pathways that promote regeneration but not tumorigenesis.

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TGF-β: A master regulator of tissue-resident macrophage identity and function

Tissue-resident macrophages exhibit remarkable plasticity, dynamically adapting to their local environment and adopting tissue-specific phenotypes that support organ homeostasis. The underlying identity-determining transcriptional programs are instructed by microenvironmental cues. Transforming growth factor-β (TGF-β), which has long been recognized for its role in immunosuppression, has recently emerged as a pivotal determinant of tissue macrophage identity. In this review, we highlight how TGF-β shapes innate immunity by driving macrophage imprinting and transcriptional programming within defined tissue niches. We emphasize that the spatial and temporal regulation of TGF-β activation—rather than its overall abundance—governs its divergent effects on immune cells. Understanding the precise mechanisms promises to spur the development of more selective therapeutic strategies for modulating macrophage function in health and disease.

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SIRT6 bridges glycolysis and epigenetics to neutrophilic asthma

Neutrophil asthma is a severe, corticosteroid-resistant subtype characterized by airway neutrophilia and declining lung function. Su et al. identify a sirtuin 6–lactate dehydrogenase A–histone lactylation axis that links macrophage glycolysis to epigenetic chemokine regulation, offering mechanistic insight into neutrophil recruitment and highlighting potential therapeutic targets.

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