The included studies were assessed as direct when a prior stressor induced a macrophage or monocyte molecular or functional state that persisted after removal of the initiating stimulus, was maintained over time or through cell division, or altered the response to a subsequent challenge. Mechanistic studies demonstrated a relevant macrophage or monocyte mechanism without directly establishing persistence or recall, while contextual studies provided broader support. The review used this evidence base to develop the Macrophage Environmental Memory Systems, or MEMS, Framework.

It organizes the literature into six non-mutually-exclusive modules: transposable element regulation, represented in 107 studies; metabolic and signaling reprogramming, in 86; epigenetic regulation, in 33; systems integration, in 17; non-coding RNA regulation, in 14; and extracellular-vesicle-mediated communication, in seven. The overlapping assignments show that the proposed mechanisms are not confined to isolated molecular layers. Transposable element regulation was the most frequently represented module, appearing in 107 of the included studies.

Metabolic and signaling reprogramming was also prominent, with 86 studies assigned to it. Epigenetic regulation appeared in 33 studies, while systems integration, non-coding RNA regulation and extracellular-vesicle-mediated communication appeared in 17, 14 and seven studies, respectively. Together, these counts map the breadth of the literature that may be relevant to acquiring, maintaining, integrating or communicating persistent macrophage states.

The authors present MEMS as an evidence-organizing and hypothesis-generating framework rather than a validated six-component biological pathway. Its purpose is to bring together research that has developed across trained immunity, epigenetic regulation, non-coding RNAs, transposable elements, extracellular vesicles and immunometabolism. The framework does not establish that every module contributes causally to environmental memory, nor does it demonstrate that all six operate together as a single process.

The review also introduces the Macrophage-Mediated Molecular Memory, or M3, hypothesis. This is described as a downstream, experimentally testable extension of MEMS involving the possible communication of environmentally acquired molecular information. It is distinct from the evidence establishing the MEMS Framework itself and remains a hypothesis rather than a demonstrated mechanism.

Future work must determine which mechanisms causally establish and maintain persistent macrophage states. The authors specifically call for exposure-withdrawal studies, longitudinal observations, lineage tracing, perturbational experiments and rechallenge studies. These designs would address the central evidential problem identified by the review: showing not only that macrophages respond to environmental conditions, but that a state persists after the initiating stimulus is removed or that the cells respond differently to a subsequent challenge.

Overall, the systematic review supports the existence of numerous candidate molecular processes that may be relevant to macrophage environmental memory, while finding comparatively little direct evidence of persistence or altered subsequent responses. The MEMS Framework consolidates a scattered literature into six interacting areas for further testing, but the review’s restrictive conclusion is equally important: the biological plausibility of candidate mechanisms has not yet been matched by broad, direct demonstration that macrophages retain an environmental memory.

Subject of Research: Systematic review of molecular evidence for persistent environmental memory in macrophages and monocytes

Article Title: Environmental memory in macrophages: a PRISMA-guided systematic review and the macrophage environmental memory systems framework

Article References: Ruden, D. M. (2026). Environmental memory in macrophages: a PRISMA-guided systematic review and the macrophage environmental memory systems framework. Frontiers in Systems Biology, 6, 1955135. https://doi.org/10.3389/fsysb.2026.1955135

Image Credits: AI Generated

DOI: 10.3389/fsysb.2026.1955135

Keywords: macrophages, environmental memory, monocytes, systematic review, trained immunity, epigenetic regulation, transposable elements, immunometabolism, non-coding RNAs, extracellular vesicles, Environmental, memory

RNA on the outside of cells is no longer a fringe idea. Over the past several years, several groups have shown that RNAs can be modified with N-glycans and displayed on the surfaces of living cells, that surface RNAs help control neutrophil recruitment, and that RNA-binding proteins and glycoRNAs form domains on the membrane that other molecules exploit for entry. What has remained unclear is which specific RNA species sit on which primary immune cells, and whether they do anything functional. Answering that question for rare primary cell populations demanded new tools, and the team developed methods to profile, image and quantify surface RNAs in cells that are available only in limited numbers from patient blood.

Using these approaches, the researchers found that members of the Y RNA family, small noncoding RNAs encoded in the genome and classically bound by the Ro60 autoantigen, preferentially localize to the surface of human monocytes, the circulating precursors of macrophages that stand at the front line of innate immunity. Confocal and super-resolution imaging of live cells, using fluorescent DNA probes complementary to RNY1, RNY3, RNY4 and RNY5 in an intact-surface FISH protocol, showed Y RNA signal colocalizing with plasma membrane markers. Flow cytometry confirmed that monocytes and B cells carry far more surface Y RNA signal than T cells, and transcriptomic comparison of surface-Y-RNA-positive versus negative monocytes revealed that the positive fraction expressed higher levels of membrane protein genes and interleukin and chemokine transcripts.

The clinical hook came from an exploratory pooled cohort of patients with inflammatory bowel disease. The proportion of peripheral monocytes positive for surface Y RNAs was markedly higher in patients with Crohn’s disease or ulcerative colitis than in healthy donors or individuals with irritable bowel syndrome. The separation was strong enough that the surface-Y-RNA-positive monocyte ratio performed well as a diagnostic discriminator, with a receiver operating characteristic area under the curve of 0.924, a cutoff of 0.17, sensitivity of 0.815 and specificity of 0.900. B cells from the same patients also showed elevated frequencies of surface-Y-RNA-positive cells, though the monocyte signal was the more striking separator between inflammatory bowel disease and the non-inflammatory controls.

Correlation is not mechanism, so the team went after what these surface RNAs actually do. A key clue came from extracellular histones, the DNA-packaging proteins that escape from dying cells and circulate as damage-associated molecular patterns. Histones are known to drive lethal inflammation in sepsis and organ injury largely through the Toll-like receptors TLR2 and TLR4, and neutrophil extracellular trap density correlates with histopathological severity in Crohn’s disease. The researchers found that fluorescently labeled histones bound abundantly to monocytes, and that this binding collapsed when surface RNAs were destroyed with RNase A and T1 or removed with a targeted depletion strategy. Strikingly, the same treatments had no effect on histone binding to B cells or other peripheral blood mononuclear cells, pointing to a monocyte-specific, RNA-dependent capture mechanism.

Biochemistry supported a direct interaction. A modified RNA interacting protein capture assay identified histones among the proteins associated with surface Y RNA, and purified assays showed that Y5 RNA binds the H2A-H2B and H3-H4 histone complexes with saturable kinetics, confirmed by gel shift experiments. In other words, Y RNAs appear to act as membrane-tethered adapters that grab extracellular histones and hold them at the monocyte surface, positioning them for recognition by innate immune receptors.

Downstream of that capture, the consequences are inflammatory. When monocytes or THP-1 macrophage-like cells were stimulated with histones, IL6 mRNA and secreted IL-6 protein rose sharply. Silencing RNY1, RNY3, RNY4 or RNY5 with antisense oligonucleotides, degrading surface RNA with RNase A and T1, or blocking TLR signaling with the inhibitor sparstolonin B all blunted that induction, while control oligonucleotides did not. Reporter and signaling assays traced the effect to activation of NF-κB and AP-1, the canonical transcriptional drivers of inflammatory cytokine output. Super-resolution imaging added a spatial dimension: Y RNAs accumulated in the same membrane nanoclusters as TLR4 and TLR2, but not with unrelated membrane proteins such as CD98, TLR5 or TLR10, and preincubating histones with in vitro-transcribed Y RNAs disrupted their colocalization with TLR4, consistent with a competition for binding that maps onto the RNA-histone interface.

The therapeutic implication was tested in the standard dextran sulfate sodium model of colitis. The team developed a depletion strategy, dubbed HASTE, that combines antisense oligonucleotides complementary to Y RNAs with RNase H to eliminate surface Y RNAs without needing to transfect cells. In vitro validation on gel and in human peripheral blood mononuclear cells confirmed that the approach selectively removed surface Y RNA signal while sparing unrelated surface RNAs such as MT-RNR2 and XIST. In mice with DSS-induced colitis, in vivo HASTE efficiently eliminated surface Y RNAs from monocytes, and treated animals showed ameliorated disease activity compared with mice receiving a control antisense oligonucleotide. B cell function appeared largely untouched, since depleting surface Y RNAs did not detectably alter apoptosis or necrosis in anti-IgM-stimulated primary B cells, and the damage-associated molecule HMGB1 still induced IL6 in a Y-RNA-independent manner, suggesting the mechanism is comparatively specific to histone sensing.

The study arrives amid a rapid expansion of interest in cell-surface RNA biology, from the discovery of glycoRNA to reports that surface RNAs form ternary complexes with RNA-binding proteins and heparan sulfate to recruit immune receptors, and that glycoRNA complexed with heparan sulfate regulates VEGF-A signaling. Y RNAs themselves have a long history: they are required for chromosomal DNA replication in human cells, they are the RNA components of Ro60 ribonucleoprotein particles, and Ro60 requires Y3 RNA for cell surface exposure in the cardiac manifestations of neonatal lupus. The new work extends that autoimmunity connection into a mechanistic role in innate immune signaling, and the authors note that histones may also associate nonspecifically with membranes and that additional surface RNAs or cofactors may contribute to histone capture and presentation.

Several caveats temper the enthusiasm. The human cohort was exploratory and pooled, so the diagnostic performance of the surface-Y-RNA-positive monocyte ratio will need validation in larger, independent cohorts before it could inform clinical practice. The mouse experiments rely on a chemically induced colitis model, which recapitulates some but not all features of human inflammatory bowel disease. And the precise molecular architecture of the Y RNA-histone-TLR complex, including which RNA regions contact histones and how the nanoclusters assemble, remains to be resolved. Even so, the study establishes a concrete function for a specific RNA species on the surface of a primary immune cell, offers a plausible mechanistic bridge between cell death, extracellular histones and cytokine storm in the gut, and demonstrates that the amplifier can be silenced. Sequencing data from the human and mouse experiments are publicly available, and the analysis code has been released, giving the field the raw material to test how broadly this surface RNA logic extends across immunity.

Subject of Research: Cell-surface Y RNAs on human monocytes amplify histone-triggered innate immune signaling in inflammatory bowel disease

Article Title: Monocyte surface Y RNAs potentiate innate immunity

Article References: Jiang, X., He, W., Xu, C., Zheng, W., Li, C., Xu, D., Shao, Q., Li, Y., Liu, Z., Li, W., He, S., Wang, Z., Liu, R., Chu, Y., Luo, Z., Huang, X., Liu, J., Yang, E., & Hu, L. (2026). Monocyte surface Y RNAs potentiate innate immunity. Nature Cell Biology. https://doi.org/10.1038/s41556-026-02100-w

Image Credits: AI Generated

DOI: 10.1038/s41556-026-02100-w

Keywords: Y RNAs, monocytes, innate immunity, inflammatory bowel disease, extracellular histones, TLR2, TLR4, NF-κB, IL-6, glycoRNA, colitis, noncoding RNA

The intellectual roots of the idea reach back further than most readers might expect. As early as 1931, researchers hypothesized that bacillus Calmette–Guérin (BCG) vaccination could reduce neonatal mortality through nonspecific stimulation of the immune system, an effect that could not be explained by protection against tuberculosis alone. The concept of trained immunity was formally articulated in the twenty-first century, when studies showed that monocytes exposed to certain microbial components responded more vigorously to a second, unrelated challenge. Interest surged again during the COVID-19 pandemic, when clinical observations revived the question of whether BCG vaccination might confer broad, heterologous protection against viral infections. The new review, led by Liqi Liao, Yong-Xian Cheng and Xuhan Liu, places these threads into a single conceptual framework spanning cellular basis, inducing factors and the full disease spectrum.

At the cellular level, trained immunity is not confined to circulating monocytes and macrophages. The review emphasizes that hematopoietic stem and progenitor cells in the bone marrow can themselves be trained, generating myeloid progeny with an enhanced inflammatory repertoire long after the initial stimulus has cleared. BCG vaccination in humans has been shown to reprogram the hematopoietic progenitor compartment, and animal studies demonstrate that trained hematopoietic stem cells generate protective innate immunity against tuberculosis. Tissue-resident macrophages, natural killer cells, innate lymphoid-like cells and dendritic cells have all been shown to display memory-like behavior under appropriate stimulation. Even organisms lacking adaptive immunity, from invertebrates to plants, exhibit forms of innate immune memory, suggesting that this is an ancient defense strategy rather than a mammalian novelty.

The triggers of trained immunity are diverse. Pathogen-associated molecular patterns such as β-glucan from fungal cell walls and lipopolysaccharide from bacterial membranes can induce the trained state, as can damage-associated molecular patterns released by injured tissue. Oxidized low-density lipoproteins, oxidized phospholipids carried on lipoprotein(a), and even catecholamines released during stress have been shown to train monocytes toward a proinflammatory phenotype. The Western diet, rich in fat and sugar, triggers NLRP3-dependent innate immune reprogramming, effectively training the immune system toward chronic metaflammation. This breadth of inducers explains why trained immunity is now implicated far beyond infectious disease, in atherosclerosis, metabolic syndrome and cancer.

Mechanistically, the review centers on what its authors call the epigenetic-metabolic axis. Upon stimulation, innate immune cells activate the mTOR–HIF-1α signaling cascade, driving a shift from oxidative phosphorylation toward aerobic glycolysis, a metabolic signature once considered exclusive to cancer cells. This metabolic rewiring is not merely fuel for the cell; it directly shapes the epigenetic landscape. Accumulated glycolytic intermediates and altered flux through the tricarboxylic acid cycle influence the availability of substrates and cofactors for chromatin-modifying enzymes, linking cellular energetics to gene regulation in a feedback loop that can persist for weeks to months.

Two histone modifications emerge as central players. Trimethylation of histone H3 at lysine 4 (H3K4me3) and acetylation at lysine 27 (H3K27ac) mark promoters and enhancers of inflammatory genes, keeping them in a poised state that allows rapid transcription upon re-exposure to a stimulus. The mevalonate and cholesterol biosynthesis pathways provide a second metabolic route into this program: activation of these pathways in trained monocytes drives both histone modifications and long-term functional changes. One-carbon metabolism, which supplies S-adenosylmethionine for methylation reactions, and NAD+-dependent sirtuins further couple metabolic state to chromatin structure. Long noncoding RNAs positioned near immune genes and three-dimensional chromatin architecture, including topologically associated domains, add additional layers of regulation that keep trained cells ready for action.

The protective face of trained immunity is best illustrated by BCG. Vaccination induces NOD2-dependent epigenetic reprogramming of monocytes, producing enhanced cytokine responses to unrelated pathogens. Randomized trials, including the ACTIVATE study in elderly individuals, showed that BCG vaccination increased the time to first infection, and experimental challenge studies demonstrated reduced viremia after yellow fever vaccination in BCG-vaccinated volunteers. Animal work extends the principle: intravenous BCG protects mice against lethal SARS-CoV-2 challenge, mucosal BCG and MTBVAC vaccination induce stronger trained immunity than standard intradermal routes, and trained alveolar macrophages in the lung confer prolonged antibacterial and antitumor protection. β-glucan-induced trained immunity has been shown to protect against Leishmania infection and to promote antitumor granulopoiesis, while trained macrophages can even confer heterologous protection against gram-negative bacteria after Staphylococcus aureus exposure.

Yet the same machinery can turn against the host. In atherosclerosis, oxidized low-density lipoprotein trains monocytes and macrophages to produce sustained proinflammatory cytokines and form foam cells, embedding a proinflammatory memory in the arterial wall. Myocardial infarction itself drives trained immunity of monocytes, accelerating subsequent atherosclerosis, and maladaptive training of myelopoiesis has been shown to link inflammatory comorbidities. In certain tumor microenvironments, trained or lipid-associated macrophages facilitate cancer progression rather than restraint. Chronic interleukin-1 exposure pushes hematopoietic stem cells toward precocious myeloid differentiation at the expense of self-renewal, a shift that can undermine long-term immune resilience. The review stresses that the outcome of trained immunity is strictly context-dependent: the identical epigenetic-metabolic program that accelerates pathogen clearance in acute infection can fuel disease progression when the stimulus is chronic.

This duality opens a therapeutic frontier. Host-directed therapies could deliberately induce trained immunity to boost vaccine efficacy or enhance antimicrobial defense, using agents such as β-glucan particles, bacterial outer membrane vesicles, or nanobiologics that deliver trained-immunity-promoting signals. Conversely, dampening pathological training could treat cardiovascular disease, with the mevalonate pathway, mTOR signaling and specific histone-modifying enzymes such as lysine methyltransferases and demethylases serving as druggable nodes. In oncology, strategies that retrain pro-metastatic macrophages or combine trained-immunity-inducing nanoparticles with checkpoint inhibitors have already shown promise in preclinical models. Compounds such as oroxylin A, which promotes LC3-associated phagocytosis in trained macrophages, hint at pharmacological routes to harness the process.

The authors argue that single-cell RNA sequencing, multi-omics profiling and systems approaches will be essential to translate these insights into precision immunology, identifying which patients stand to benefit from immune training and which are at risk from it. Recent multi-omics work on BCG vaccination has already revealed epigenetic cell states that predict the strength of the trained response in individuals, a first step toward personalized vaccination strategies. As the field matures, trained immunity is shifting from a provocative concept to a practical framework: one that reframes immune memory as a continuum spanning innate and adaptive systems, and one whose manipulation, the review concludes, could reshape the prevention and treatment of infectious, inflammatory and oncological disease alike.

Subject of Research: The epigenetic and metabolic mechanisms of trained immunity and their dual roles in infection, chronic inflammation and cancer

Article Title: The epigenetic-metabolic axis of trained immunity: dual roles in disease pathogenesis and intervention

Article References: Liao, L., Zhai, Z., Zhong, L., Shi, C., Yao, S., Tao, L., Cheng, Y.-X., & Liu, X. (2026). The epigenetic-metabolic axis of trained immunity: dual roles in disease pathogenesis and intervention. Journal of Molecular Medicine, 104(1), Article 121. https://doi.org/10.1007/s00109-026-02729-y

Image Credits: AI Generated

DOI: 10.1007/s00109-026-02729-y

Keywords: trained immunity, epigenetic reprogramming, metabolic rewiring, BCG vaccine, innate immune memory, mTOR-HIF-1α signaling, histone modification, mevalonate pathway, atherosclerosis, cancer immunotherapy, monocytes, hematopoietic stem cells

The challenge that motivated the work is well known to cardio-oncologists. When a patient receiving checkpoint inhibitors develops chest pain, arrhythmias, or rising cardiac troponin levels, clinicians must distinguish true ICI-myocarditis from other causes of cardiac stress in a cancer population. Current diagnosis relies heavily on biomarkers, electrocardiography, cardiac magnetic resonance imaging, and, in severe cases, endomyocardial biopsy, which is invasive and rarely performed early. Without a clear molecular understanding of what the immune system is actually doing during the attack on heart muscle, the field has lacked both precise diagnostics and rational targeted therapies. The Shanghai group set out to close that gap by examining immune cells directly, at single-cell resolution, in patients before and after the onset of disease.

Using single-cell RNA sequencing of peripheral blood mononuclear cells, the researchers profiled the circulating immune compartment of patients with ICI-myocarditis and compared it with that of cancer patients receiving checkpoint inhibitors who remained free of cardiac toxicity. The analysis revealed a striking expansion of a subset of CD8-positive T cells expressing ISG15, a protein induced by type I interferon signaling. These ISG15-positive CD8 T cells carried a strongly proinflammatory transcriptional program, suggesting they were not passive bystanders but active participants in the autoimmune assault on the myocardium. The finding was consistent across patients and was corroborated by independent flow cytometry measurements of the same cell populations.

Crucially, the ISG15-positive T cells did not appear to act alone. The single-cell data showed that their abundance at baseline correlated with proinflammatory features in monocytes, the innate immune cells that can amplify tissue damage through cytokine release and antigen presentation. Computational analysis of ligand-receptor interactions across cell types suggested that the communication between these two compartments may be mediated, at least in part, by the CCL2-CCR2 chemokine axis, a well-characterized signaling pathway that recruits monocytes expressing the CCR2 receptor toward sites of inflammation. In other words, the T cells appeared to summon and activate the monocytes, creating a self-reinforcing inflammatory loop in the heart.

To test whether these circulating cells were genuinely cardiotoxic rather than merely correlated with disease, the team performed in vitro experiments. They isolated the ISG15-positive CD8 T cells from patient blood and co-cultured them with cardiomyocytes, observing that these cells showed a high potential to induce apoptosis, or programmed cell death, in the heart muscle cells. This functional evidence supports the pathogenic role that the transcriptional data had implied: the very cells enriched in patients who develop myocarditis carry the molecular machinery to kill cardiomyocytes. It is a direct demonstration, at the cellular level, of how checkpoint inhibitor therapy can tip the immune system toward self-destruction of cardiac tissue.

The translational payoff of the study comes in two forms. The first is diagnostic. Based on the inflammatory signature identified in the multi-omics data, the researchers developed a custom panel of eight proteins measurable in blood, selected from the proteomic and cytokine profiles that distinguished ICI-myocarditis patients from other checkpoint inhibitor-treated controls. The panel showed promising performance in separating true myocarditis from patients on the same drugs who did not develop cardiac toxicity. If validated in larger, prospective cohorts, such a panel could allow oncologists and cardiologists to identify or rule out ICI-myocarditis earlier and with greater confidence than current biomarkers alone, potentially preventing the delays that contribute to the condition’s high fatality rate.

The second payoff is therapeutic. The integrated analysis pointed to JAK-STAT signaling, a central intracellular pathway downstream of many inflammatory cytokine receptors, as a shared driver of the inflammatory programs in both the ISG15-positive CD8 T cells and the activated monocytes. In mouse models of ICI-induced cardiac injury, pharmacological inhibition of the JAK-STAT pathway ameliorated cardiac dysfunction and reduced inflammatory infiltration into the heart. Remarkably, the intervention did not simply blunt the autoimmune attack; it also enhanced the response to anti-PD-1 therapy in the same models. That dual effect is significant because the ideal treatment for ICI-myocarditis would suppress the cardiac toxicity without sacrificing the anti-tumor benefit that motivated checkpoint blockade in the first place.

The chemokine axis offered a parallel therapeutic target. When the researchers blocked the CCL2-CCR2 axis in vivo, the intervention attenuated ICI-induced cardiac injury in the animal models, consistent with the idea that disrupting the recruitment of CCR2-expressing monocytes can break the inflammatory loop that damages the myocardium. Together, the JAK-STAT and CCL2-CCR2 findings suggest that ICI-myocarditis is not an undifferentiated inflammatory storm but a structured pathological circuit with defined nodes that can be pharmacologically intercepted. Each node represents a potential drug target, and several JAK inhibitors and CCR2 antagonists already exist in the clinical pharmacology arsenal for other inflammatory diseases, which could accelerate the path to clinical testing.

The study also carries implications for risk prediction before therapy begins. The observation that high levels of baseline ISG15-positive CD8 T cells are linked to the development of myocarditis raises the possibility of screening patients before they start checkpoint inhibitors, identifying those whose immune systems are already primed for interferon-driven, cytotoxic anti-cardiac responses. Such pre-treatment stratification remains speculative until prospective studies confirm the predictive value of the signature, but it fits a broader trend in immuno-oncology toward tailoring therapy to a patient’s baseline immune state rather than reacting to toxicity after it appears.

Cautions remain. The human findings rest on peripheral blood measurements, which serve as a window into the immune response but do not fully capture the inflammatory milieu inside the heart muscle itself, where tissue-resident immune populations may behave differently. The mouse models, while supportive, recapitulate only parts of the human disease. And the eight-protein diagnostic panel, however promising, will need rigorous external validation across diverse cancer types, treatment regimens, and ethnic populations before it can enter routine clinical use. Nevertheless, by integrating single-cell transcriptomics, proteomics, cytokine profiling, and functional experiments into a single coherent picture, the Zhongshan Hospital team has converted a poorly understood, frequently fatal complication into a molecularly defined disease with identifiable cellular culprits, a candidate blood-based diagnostic, and two mechanistically grounded therapeutic strategies. For the growing population of patients whose cancers are treated with checkpoint inhibitors, that transformation is a meaningful step toward making immunotherapy’s most dangerous side effect predictable, detectable, and treatable.

Subject of Research: Immune mechanisms, diagnosis, and treatment of immune checkpoint inhibitor-induced myocarditis

Article Title: Integrated multi-omics identifies distinct immune signatures with diagnostic and therapeutic implications in immune checkpoint inhibitor-induced myocarditis

Article References: Zhang, S.-L., Cai, Q.-Q., Zhang, J., Liu, Y., Lu, H., Zhang, Y.-R., Xu, Y.-C., Peng, H.-X., Chen, H.-Y., Wang, Y., Cheng, L.-L., & Ge, J.-B. (2026). Integrated multi-omics identifies distinct immune signatures with diagnostic and therapeutic implications in immune checkpoint inhibitor-induced myocarditis. Nature Communications. https://doi.org/10.1038/s41467-026-77262-0

Image Credits: AI Generated

DOI: 10.1038/s41467-026-77262-0

Keywords: immune checkpoint inhibitors, myocarditis, CD8 T cells, ISG15, monocytes, CCL2-CCR2 axis, JAK-STAT pathway, single-cell RNA sequencing, proteomics, cardiotoxicity, cancer immunotherapy, biomarkers

The research, led by Flavio Donnini and Paolo Tini at the University of Siena in collaboration with investigators across multiple Italian institutions, focused not on static pretreatment values, which most prior studies have examined, but on the dynamic trajectory of circulating monocytes during treatment itself. The team defined a metric they call monocytic resilience: the log2-transformed ratio of the absolute monocyte count measured at the end of chemoradiotherapy to the count measured before treatment began. In essence, the measure captures whether a patient’s monocyte compartment is preserved, depleted, or expanded by the combined assault of radiation and chemotherapy—a biological signature of how the host immune system weathers one of the most demanding treatment courses in oncology.

The retrospective cohort included 127 adults with histologically confirmed IDH-wildtype glioblastoma, the molecularly defined subtype that carries the poorest prognosis and accounts for the vast majority of glioblastoma diagnoses in adults. Of these, 115 patients had complete monocyte trajectories and overall survival data, and the primary adjusted statistical model encompassed 102 patients among whom 86 deaths occurred. The investigators deliberately designed their analysis to ask whether the monocyte ratio carried prognostic weight beyond the factors clinicians already use, adjusting their models for MGMT promoter methylation, gross total resection, Karnofsky Performance Status, and age, and additionally accounting for baseline monocyte burden, changes in lymphocyte counts, systemic inflammatory imbalance, and measured corticosteroid exposure.

The results were striking. When analyzed as a continuous variable, the post-treatment to pre-treatment monocyte ratio was independently associated with overall survival, with a hazard ratio of 0.53 per doubling of the ratio (95 percent confidence interval 0.37 to 0.76; p = 0.00051). In practical terms, each doubling of the monocyte ratio was associated with nearly a halving of the risk of death during the observation period, an effect size that rivals or exceeds many molecular biomarkers currently in clinical use. The signal survived every adjustment the investigators applied, suggesting that the preservation of circulating monocytes during treatment reflects a genuine host-response phenotype rather than a statistical artifact of tumor aggressiveness or treatment intensity.

To make the finding clinically interpretable, the team also evaluated an exploratory threshold: a post/pre ratio of 0.75, meaning that patients whose end-of-treatment monocyte count remained at or above 75 percent of their pretreatment value were classified as having preserved monocytic resilience. Using this cutoff, 52 patients fell into the low-resilience group and 63 into the preserved-resilience group. The separation in survival was dramatic: median overall survival was 10.2 months in the low-resilience group compared with 17.3 months in the preserved-resilience group, a difference of roughly seven months detected with a log-rank p value of 0.00064. In univariable Cox analysis, preserved resilience was associated with a 50 percent reduction in mortality (hazard ratio 0.50, 95 percent confidence interval 0.34 to 0.75; p = 0.00080).

Importantly, the investigators were careful about how they handled the threshold itself. Recognizing the well-documented statistical pitfalls of dichotomizing continuous variables, they treated the continuous ratio as the primary basis for inference and used the 0.75 cutoff only for exploratory visualization and sensitivity analysis. They also employed bootstrap resampling to probe whether the apparent threshold was an artifact of their particular dataset. The outcome-optimized cut-points clustered tightly around the same region, with a median of 0.74 and an interquartile range of 0.70 to 0.81, lending credibility to the choice of 0.75 as a clinically meaningful boundary—while the authors explicitly caution that the threshold remains exploratory and requires external validation before any clinical application.

The biological rationale behind the finding is grounded in a growing body of literature on systemic immune perturbation in glioblastoma. Monocytes are innate immune cells that circulate in the blood and give rise to macrophages, including the tumor-associated macrophages and microglia that can constitute up to a third of the cellular mass of a glioblastoma. Prior work has shown that glioblastoma patients exhibit profound systemic immune suppression, including an expansion of immunosuppressive CD14-positive HLA-DR-low monocytes, and that dexamethasone—the corticosteroid nearly universally prescribed to control peritumoral edema—reshapes the monocyte compartment in ways that may promote tumor progression. Studies have also demonstrated that T cells become sequestered in the bone marrow in the setting of intracranial tumors, and that treatment-induced lymphopenia during chemoradiotherapy is strongly associated with worse survival, partly driven by radiation exposure of circulating blood and by cumulative corticosteroid dose.

What makes the new finding conceptually distinct is that it isolates the monocyte lineage from the lymphocyte story that has dominated the field. The Siena team adjusted for lymphocyte change and for systemic inflammatory indices, yet the monocyte ratio retained its independent association with survival. This suggests that monocytic resilience is not simply a proxy for overall bone marrow reserve or for the degree of treatment-related immunosuppression, but may capture something specific about the interplay between the tumor, the treatment, and the innate immune system. Whether preserved monocytes reflect a less inflammatory tumor microenvironment, a more favorable corticosteroid exposure profile, an intrinsic host capacity to regenerate myeloid cells, or some combination of these mechanisms remains an open question that the authors themselves flag as requiring immune phenotyping studies.

The practical appeal of the metric is difficult to overstate. Unlike genomic classifiers or advanced imaging biomarkers, absolute monocyte counts are obtained routinely, inexpensively, and reproducibly in every complete blood count. A patient undergoing the standard Stupp regimen already has blood drawn before treatment and at its conclusion, meaning that monocytic resilience could, in principle, be calculated from data that already exist in the medical record. If validated prospectively, the measure could help stratify patients for clinical trials, identify individuals who might benefit from intensified surveillance or adaptive treatment strategies, and provide an early pharmacodynamic readout of how a patient’s immune system is responding to therapy—information that currently arrives far too late in the form of surveillance MRI.

The authors are appropriately measured in their conclusions. This was a retrospective, single-country cohort study, and the exploratory threshold of 0.75 has not been tested in an independent population. Medication-level confounder assessment—particularly granular corticosteroid dosing data—and prospective validation in external cohorts are explicitly required before the metric can inform clinical decisions. Yet the study exemplifies a broader and increasingly exciting trend in neuro-oncology: the recognition that the peripheral immune system is not a passive bystander in brain cancer but an active participant whose dynamics over time encode prognostic information. As immunotherapeutic strategies for glioblastoma continue to struggle in clinical trials, simple, dynamic, and accessible markers of host immune resilience such as this one may prove essential not only for prognosis but for rationally selecting which patients might benefit from the next generation of immune-based treatments.

Subject of Research: Monocyte count trajectories during chemoradiotherapy as a prognostic biomarker for survival in IDH-wildtype glioblastoma

Article Title: Monocytic resilience during chemoradiotherapy is independently associated with survival in IDH-Wildtype glioblastoma

Article References: Donnini, F., Pastina, P., Battaglia, G., Chibbaro, S., Cerase, A., Nardone, V., Desideri, I., Pasqualetti, F., Pascucci, A., D’Alonzo, V., Mazzei, M. A., Minniti, G., Di Giacomo, A. M., & Tini, P. (2026). Monocytic resilience during chemoradiotherapy is independently associated with survival in IDH-Wildtype glioblastoma. Journal of Neuro-Oncology, 180(1), Article 15. https://doi.org/10.1007/s11060-026-05830-x

Image Credits: AI Generated

DOI: 10.1007/s11060-026-05830-x

Keywords: glioblastoma, monocytes, immune resilience, chemoradiotherapy, biomarkers, survival, corticosteroids, temozolomide, prognosis, neuro-oncology, blood counts, MGMT methylation

The central surprise of the study lies in the asymmetry of this crosstalk. When the team exposed human monocytes and macrophages to TNF and IL-4 together, they expected the classic pattern of mutual cross-inhibition that has dominated the literature on antagonistic cytokine pairs. What they observed instead was cooperation. TNF functioned predominantly as a partner that expanded and intensified the set of genes switched on by IL-4, rather than as a brake. The interleukin’s own signature was not blunted by the presence of the inflammatory signal; it was broadened by it. This finding suggests that the anti-inflammatory cytokine does not merely survive contact with its proinflammatory counterpart but actively exploits TNF signaling to shape the scope of its own transcriptional output.

The selectivity of the reverse direction is equally striking. IL-4 did not shut down TNF signaling wholesale. Instead, it targeted a specific component of the TNF-induced program: the interferon response. Genes driven by interferon regulatory pathways, which form an important antimicrobial and immune-activating arm of TNF signaling, were selectively inhibited by IL-4. The broader inflammatory gene expression elicited by TNF, however, remained largely intact. In other words, IL-4 pruned the interferon branch of the TNF response while leaving the rest of the inflammatory tree standing. This level of precision implies that the two cytokines negotiate at the level of individual gene programs rather than through a simple global on-off switch.

Among the genes that responded synergistically to the combined cytokines were sets with well-recognized roles in regulating inflammation and promoting tissue repair. When TNF and IL-4 were present together, these gene sets were induced to levels far exceeding what either cytokine achieved alone. The synergy was not a minor quantitative effect confined to a handful of transcripts; it encompassed coordinated gene programs that shape how macrophages behave in damaged tissue. Because macrophages are central orchestrators of the transition from inflammation to repair, the identity of the genes governed by this combined signal carries weight for understanding how wounds progress from the inflammatory phase to the rebuilding phase.

To test whether this laboratory-scale crosstalk mattered in a living tissue context, the investigators turned to a skin wound-healing model. Their analysis revealed that the synergistically induced gene sets were highly expressed during precisely the phase of wound repair when TNF and IL-4 are co-expressed in the healing tissue. This temporal overlap is biologically meaningful. It suggests that the cooperative program observed in cultured human monocytes is not an artifact of the dish but reflects a naturally occurring transcriptional state in which the two cytokines act together in time and space. During the window when inflammation and repair must be balanced, the combined TNF and IL-4 signal appears to help define the macrophage phenotype that supports that balance.

Mechanistically, the study traced the crosstalk to epigenetic chromatin-mediated mechanisms rather than to changes in signaling alone. Transcription factors are the proteins that bind DNA and switch genes on, but whether they can reach their targets depends on the state of the chromatin, the packaged form of DNA in the cell. The researchers found that cooperation between NF-κB, the canonical transcription factor activated by TNF, and STAT6, the transcription factor activated downstream of the IL-4 receptor, underpinned the synergistic gene expression. Rather than acting through separate gene sets, these two pathways converged on shared regulatory elements, allowing a proinflammatory signal and an anti-inflammatory signal to jointly open and activate the same loci.

A second epigenetic mechanism involved the erasure of a repressive histone mark. Histone H3 lysine 27 trimethylation, abbreviated H3K27me3, is a chemical modification of chromatin that is generally associated with silenced or po genes held in a inactive state. In the presence of the combined cytokine signal, this negative mark was removed from relevant genomic regions, lifting a layer of repression and permitting transcriptional activation. The removal of H3K27me3 provides a plausible explanation for how the synergy produces gene induction that neither cytokine can accomplish alone: TNF signaling through NF-κB helps remodel the chromatin landscape in a way that makes IL-4-driven, STAT6-dependent transcription possible at genes that would otherwise remain closed.

The third mechanistic pillar was the selective inhibition of IRF1, a transcription factor that mediates interferon responses and contributes to the interferon arm of TNF signaling. By suppressing IRF1, IL-4 was able to disassemble the interferon component of the TNF program without dismantling TNF-driven inflammatory gene expression more broadly. This selective targeting helps explain the otherwise paradoxical combination of results: cooperation at repair-related and inflammation-regulating genes on one hand, and selective antagonism at interferon-responsive genes on the other. The crosstalk is therefore not a single mechanism but a coordinated set of chromatin-level events that produce different outcomes at different classes of target genes.

The authors frame these results as identifying a mechanism for the expansion of the IL-4 response, and the implications extend beyond basic cytokine biology. If TNF signaling is required for the full breadth of the IL-4 program in monocytes and macrophages, then broadly suppressing TNF, as many anti-TNF therapies do in conditions such as rheumatoid arthritis and inflammatory bowel disease, may have consequences that reach into the tissue-repair arm of immunity, not only the inflammatory arm. The study also highlights the complexity of crosstalk between antagonistic cytokines more generally, showing that pairs of signals long assumed to cancel each other out can instead cooperate on select gene responses that are important for immune function and tissue repair. Cross-inhibition, the traditional focus of the field, turns out to be only part of the story.

As with any study, the findings come with scope conditions worth keeping in view. The human cell work was performed in primary monocytes and macrophages, and the in vivo evidence comes from a skin wound-healing model, so extending the conclusions to other tissues, other disease settings, and other cytokine combinations will require further investigation. Nevertheless, the work offers a concrete and testable framework: antagonistic cytokines negotiate through transcription factor cooperation, targeted histone modification, and selective inhibition of intermediary factors such as IRF1. For a field that has long organized itself around the idea that inflammatory and anti-inflammatory signals are opponents, the demonstration that TNF can serve as a costimulator of the IL-4 program, and that the two jointly govern genes central to repair, is a reminder that the immune system’s wiring is built less on simple opposition than on context-dependent partnership.

Subject of Research: Crosstalk between the cytokines TNF and IL-4 in regulating gene expression in human monocytes and macrophages

Article Title: IL-4 exploits TNF signaling to shape its gene expression signature in monocytes and macrophages

Article References: Yuan, R., Yang, C., Mishra, B., Oliver, D., Bell, R. D., & Ivashkiv, L. B. (2026). IL-4 exploits TNF signaling to shape its gene expression signature in monocytes and macrophages. Nature Communications. https://doi.org/10.1038/s41467-026-78528-3

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78528-3

Keywords: IL-4, TNF, monocytes, macrophages, cytokine crosstalk, NF-kB, STAT6, H3K27me3, IRF1, gene expression, wound healing, immunology

A new study published in iScience by Eva Dervas of the University of Zurich and colleagues set out to test that long-standing assumption directly. The researchers assembled a remarkable cohort of 133 captive boa constrictors drawn from breeding colonies, private collections, and a reptile shelter in Switzerland and Germany. Using blood smears, the gold standard diagnostic method, they identified 49 animals with BIBD based on the presence of inclusion bodies in peripheral blood cells. A multiplex reverse transcription PCR confirmed reptarenavirus infection in every one of those animals and, crucially, identified three additional snakes that carried viral RNA without any detectable inclusion bodies, making them asymptomatic carriers. The remaining 83 animals tested negative for both disease and virus. The cohort spanned ages from three months to 25 years, allowing the team to disentangle the effects of disease from those of normal aging and sex.

The researchers hypothesized that BIBD compromises both innate and adaptive immune functions, and that these impairments would be reflected in altered blood parameters, impaired antibody responses, and elevated stress hormones. To test this, they performed an unusually comprehensive battery of assays on blood and plasma samples. These included hematological and biochemical analyses, corticosterone measurements, a phagocytosis assay using fluorescent beads, lysozyme quantification, hemagglutination and hemolysis tests for natural antibodies and complement, a leukocyte blast transformation test for T cell function, and enzyme-linked immunosorbent assays for virus-specific immunoglobulins. Few studies of reptilian immunology have attempted such breadth, and the effort reflects how little is still known about how snake immune systems work.

The first striking finding concerned phagocytosis, the process by which immune cells engulf and destroy pathogens. In boa constrictors, two related cell types perform this function in the blood: monocytes and azurophils, the latter being a cell type unique to reptiles whose exact origin and function remain poorly understood. Both express Iba1, a marker of the monocyte and macrophage lineage. When the researchers incubated white blood cells with fluorescent beads, they found that BIBD-positive snakes had a significantly lower percentage of Iba1-positive cells performing phagocytosis, with a mean of 52.2 percent compared with 64.36 percent in uninfected animals. BIBD-positive snakes also had significantly fewer circulating monocytes, with a geometric mean percentage of 1.62 percent versus 2.4 percent in disease-free animals. These deficits held up after statistical correction for age, sex, and clustering by breeder, and they were also evident when animals were grouped simply by infection status rather than by disease.

This impairment of phagocytic cells is particularly intriguing when viewed against what is known about mammalian arenavirus infections. In humans infected with Lassa virus or lymphocytic choriomeningitis virus, infection and inhibition of macrophages and dendritic cells are well-documented features of disease. Lassa virus infection reduces the phagocytic activity of dendritic cells and macrophages, an effect proposed to stem from a failure of monocyte maturation. More recent work on New World arenaviruses such as Junín and Machupo viruses has uncovered mechanistic links between viral entry and phagocytosis, identifying host restriction factors like TRIM2 and SIRPA that jointly regulate both processes. Although the receptors used by reptarenaviruses to enter snake cells are still unknown, the authors suggest that the reduced phagocytic activity they observed could represent a direct consequence of the virus infecting these very cells. Notably, their earlier work showed that the inclusion body-laden cells of the bone marrow, including hematopoietic precursors, are infected in BIBD, and that monocytes and azurophils themselves carry viral inclusion bodies.

Not every component of the immune system showed damage. Lysozyme concentrations, natural antibody and complement titers measured by hemagglutination and hemolysis, and the leukocyte blast transformation response to phytohemagglutinin stimulation all remained unchanged between diseased and healthy animals. Stress markers told a similar story of stability: plasma corticosterone, glucose, and the heterophil-to-lymphocyte ratio did not differ significantly between groups, although the authors caution that variable sampling conditions, with some animals handled briefly at home and others transported before sampling, likely introduced considerable interindividual noise. The findings suggest that BIBD is not a blanket collapse of immunity but a targeted disruption, with the phagocytic arm of innate immunity bearing the brunt of the impact.

The adaptive side of the immune response revealed a more nuanced picture. Snakes with BIBD had significantly lower total plasma immunoglobulin concentrations, with a geometric mean of 11.23 percent compared with 16.97 percent in uninfected animals. Yet when the researchers measured antibodies specific to the reptarenavirus University of Giessen virus 1, the diseased snakes showed higher levels of both virus-specific IgM and IgY than uninfected animals. Using established cutoff values, 77.1 percent of BIBD-positive snakes tested positive for anti-UGV-1 antibodies, with IgM detected more frequently than IgY, an unexpected result given that IgY, the functional equivalent of mammalian IgG, is generally considered the dominant antibody class in reptiles. Interestingly, 36.7 percent of uninfected snakes also carried anti-UGV-1 antibodies, hinting at either past infections that were cleared or cross-reactive responses to undetected viruses. The authors propose several explanations for the paradox of low total immunoglobulin alongside high virus-specific titers, including general dampening of antibody production by the virus or the sequestration of antibodies into circulating immune complexes, a phenomenon documented in persistent lymphocytic choriomeningitis virus infections of mice.

Beyond immunity, the study uncovered a metabolic signature of disease. BIBD-positive snakes had significantly lower blood cholesterol than their uninfected counterparts, and the same held true when animals were grouped by infection status. The authors note that hypocholesterolemia in mammals is associated with several chronic infections, including HIV and pulmonary tuberculosis, where lower cholesterol correlates with disease severity and even mortality. Because the snakes came from multiple collections with varying husbandry and showed no significant weight loss, diet is an unlikely explanation. Instead, the researchers point to the liver: inclusion bodies form in the majority of hepatocytes in BIBD, and their previous work demonstrated that the viral nucleoprotein accumulates within the mitochondria of infected cells. Given the central role of hepatocyte mitochondria in lipid metabolism, viral-induced mitochondrial dysfunction could plausibly underlie the observed drop in cholesterol, a hypothesis the authors hope future studies will test directly.

The study also carefully separated the effects of disease from those of ordinary biological variation. Regardless of BIBD status, heterophil and azurophil percentages and hematocrit rose with age while lymphocyte percentages fell, mirroring the shift from lymphoid-dominated to myeloid-dominated hematopoiesis seen in mammals. Aspartate transaminase levels correlated with male sex rather than disease, echoing the sex differences seen in human reference ranges. These controls strengthen the conclusion that the immune and metabolic changes tied to BIBD are genuine disease effects rather than artifacts of demography. The authors acknowledge limitations, including the cross-sectional design, the small number of carrier animals, and the rarity of clinically affected individuals in the cohort, and they call for longitudinal and experimental infection studies to determine whether reduced phagocytosis precedes overt disease and could serve as an early warning sign. For now, the work delivers a clear verdict on a decades-old assumption: BIBD does alter immune function in boa constrictors, but selectively, impairing phagocytic innate defenses and reshaping antibody dynamics in ways that may finally explain why these snakes so often fall to secondary infections.

Subject of Research: Immune function alterations in boa constrictors with boid inclusion body disease caused by reptarenavirus infection

Article Title: Boid inclusion body disease in Boa constrictor : Unraveling the myth of immunosuppression

Article References: Dervas, E., Czirják, G. Á., Michalopoulou, E., Liesegang, A., Novacco, M., Schwarzenberger, F., Hetzel, U., Hepojoki, J., Baggio, F., & Kipar, A. (2026). Boid inclusion body disease in Boa constrictor: Unraveling the myth of immunosuppression. iScience, 29(10), Article 117669. https://doi.org/10.1016/j.isci.2026.117669

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117669

Keywords: boid inclusion body disease, reptarenavirus, Boa constrictor, immunosuppression, phagocytosis, innate immunity, adaptive immunity, azurophils, monocytes, cholesterol, IgY antibodies, reptile immunology

The cells in question are monocytic myeloid-derived suppressor cells, or M-MDSCs. These cells arise from monocytes, the white blood cells that normally serve as first responders and antigen presenters in the immune system. Early in sepsis, monocytes pump out inflammatory signals such as IL-1β, IL-6, and TNF-α, fueling the systemic inflammation that damages tissues. As the disease progresses, however, a subset of monocytes loses its HLA-DR surface molecules, loses its ability to present antigen, and instead begins actively suppressing other immune cells through molecules like arginase 1, indoleamine 2,3-dioxygenase, and TGF-β. The paradox has been that although this suppression might seem protective against the initial inflammatory storm, its persistence is now considered harmful, leaving patients vulnerable to secondary infections and chronic critical illness.

The central obstacle has been heterogeneity. The markers most commonly used to identify M-MDSCs, including CD33, CD11b, CD14, and low or absent HLA-DR, do not cleanly separate suppressive M-MDSCs from ordinary resting monocytes. Worse, studies of MDSCs in animal models and in humans have produced contradictory conclusions about whether these cells help or harm. In the new study, published in the Journal of Advanced Research, investigators led by Feng Wang, Fan He, and Liming Cheng enrolled 195 patients with sepsis at Tongji Hospital, dividing them into those with non-septic shock, survivors of septic shock, and non-survivors of septic shock, and then applied single-cell RNA sequencing to resolve the confusion.

The first surprise came from conventional flow cytometry. Although the percentage of HLA-DR-positive monocytes declined progressively with disease severity, and although M-MDSC frequency correlated positively with SOFA organ dysfunction scores overall, the raw abundance of M-MDSCs performed poorly as a prognostic tool, with an area under the curve of only 0.564 for distinguishing survivors from non-survivors. Even more striking, the correlation between M-MDSC frequency and SOFA score reversed direction in the patients who ultimately died. Something about the cells themselves, rather than their numbers, appeared to hold the prognostic information.

To capture that information, the team purified CD14-positive monocytes from patients classified as having either high or low HLA-DR expression and sequenced them individually on the 10x Genomics platform, integrating the data with a healthy donor control. After quality filtering, 29,545 cells yielded nine distinct transcriptional clusters, ranging from naïve and interferon-stimulated monocytes to pro-inflammatory monocytes and true M-MDSCs marked by high RETN and low HLA gene expression. Crucially, the vast majority of HLA-DR-low CD14-positive monocytes from sepsis patients proved to be authentic M-MDSCs, confirming that this clinically accessible fraction is the right place to look for the suppressive cells.

Zooming in on 11,858 M-MDSCs, the researchers identified five subsets, named for their signature genes. S100A_M-MDSCs expressed S100A12, GAPDH, and LGALS1 and were enriched for mitochondrial respiration and inflammatory response. IL1R2_M-MDSCs expressed IL1R2, FOSB, and DACH1 and showed a striking dual profile, combining positive regulation of cytokine production with negative regulation of the immune response. THBS1_M-MDSCs expressed THBS1, MTSS1, and ID2 and were dominated by TGF-β receptor signaling. Two smaller populations, an interferon-stimulated subset and a PPBP-expressing subset corresponding to monocyte-platelet aggregates, rounded out the picture. Together, the three dominant subsets accounted for roughly 90 percent of all M-MDSCs.

Pseudotime trajectory analysis then revealed that these subsets represent developmental stages rather than separate lineages. Early-stage S100A_M-MDSCs sit at the origin of the trajectory, brimming with pro-inflammatory genes. Middle-stage IL1R2_M-MDSCs and THBS1_M-MDSCs occupy a transitional zone, the former producing inflammatory mediators such as CXCL8 and IFITM2 while the latter ramps up TGF-β signaling. By the late stage, both subsets converge on a strongly immunosuppressive program, co-expressing genes such as ZEB2, FMN1, and ADAM17 that dampen immune responses. Notably, sepsis-derived M-MDSCs lacked the canonical suppressive machinery seen in cancer, including ARG1, NOS2, PD-L1, and CD73, underscoring that these cells behave differently depending on disease context.

The team also traced the transcriptional and metabolic rewiring that accompanies this maturation. Transcription factor analysis showed CEBPD and ETS1 active early, FOSB and CREB5 peaking in the middle stage, and EZH2 and FOXN3 accumulating to maximal levels late. Metabolically, early cells relied on oxidative phosphorylation and arginine metabolism, while later subsets shifted toward fatty acid biosynthesis and branched-chain amino acid metabolism. Seahorse assays confirmed that HLA-DR-low monocytes from sepsis patients had reduced basal and maximal mitochondrial respiration but elevated fatty acid synthase, a metabolic signature consistent with the transition from inflammatory monocyte to suppressive M-MDSC.

Among the markers identified, VSIG4 stood out. This surface molecule was barely detectable on monocytes from healthy donors but significantly elevated in sepsis patients, and it was specifically expressed on the suppressive THBS1_M-MDSC subset. In laboratory experiments, silencing VSIG4 in THP-1 monocyte cells boosted their production of IL-1β, IL-6, and TNF-α, while blocking VSIG4 on HLA-DR-low monocytes from sepsis patients restored the proliferation and HLA-DR expression of co-cultured CD4-positive T cells. These results establish VSIG4 as a functional marker of the suppressive state, not merely a passive correlate.

The translational payoff came when the researchers combined flow cytometric measurements of VSIG4 and IL1R2 on HLA-DR-low CD14-positive monocytes. Neither marker alone reliably separated survivors from non-survivors, but together they achieved a sensitivity of 92.3 percent and a specificity of 90 percent in the tested cohort. Using the maximum of the two values, the combined metric reached an area under the curve of 0.935, with 84.62 percent sensitivity and 93.33 percent specificity, and it outperformed SOFA score, lactate, and age in a multivariable model. A cutoff of 33 percent stratified 28-day survival in Kaplan-Meier analysis. The authors caution that the sample sizes for the sequencing and validation arms were small, that all patients came from a single center, and that longitudinal validation is still needed. Even so, the study delivers something the field has lacked: a coherent map of M-MDSC development in human sepsis, from pro-inflammatory beginnings to immunosuppressive maturity, with surface markers that can be measured in a clinical flow cytometry lab. If larger trials confirm the findings, a simple two-marker blood test could one day help clinicians identify, within days of admission, which septic patients are sliding toward the immunoparalysis that kills so many, and direct immunorestorative therapies to those who need them most.

Subject of Research: Functional heterogeneity of monocytic myeloid-derived suppressor cells in sepsis prognosis

Article Title: Illustrating the functional heterogeneity of M-MDSCs to predict sepsis outcomes

Article References: Tang, G., Xing, W., Zhu, L., Lu, Y., Jiang, K., Wu, S., Sun, Z., Hou, H., Cheng, L., He, F., & Wang, F. (2026). Illustrating the functional heterogeneity of M-MDSCs to predict sepsis outcomes. Journal of Advanced Research, 88, 807-824. https://doi.org/10.1016/j.jare.2026.01.008

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.01.008

Keywords: sepsis, septic shock, M-MDSCs, single-cell RNA sequencing, VSIG4, IL1R2, TGF-β signaling, immunosuppression, biomarkers, flow cytometry, monocytes, immunometabolism

The research team, led by senior author You Wu with co-first authors Yangxin Zhao, Fangzheng Cao, Houwen Zhang, and Yu Liang, took an unusually comprehensive approach. Rather than studying one tissue or one disease in isolation, they integrated single-cell RNA-sequencing data from both COPD lung tissue and atherosclerotic plaques, then layered on a genetic technique called cell-type-specific Mendelian randomization. This combination allowed them to move beyond correlation and ask whether the immune programs shared by the two diseases are actually causal drivers of disease risk, using human genetic variation as a natural experiment.

Single-cell RNA sequencing allows researchers to measure gene activity in thousands of individual cells at once, revealing the cellular cast of a tissue rather than a blended average. When the team applied this lens to COPD lung samples, they found the expected mosaic of epithelial, endothelial, and stromal cells, but the most striking feature was the remodeling of the myeloid compartment, the branch of the immune system that includes macrophages and monocytes. Marker-gene analysis confirmed distinct transcriptional programs in these populations, and composition analysis showed that the balance of myeloid cells was substantially shifted in diseased lungs compared with healthy tissue.

Even more revealing was the cell-to-cell communication analysis. By mapping ligand-receptor interactions between cell populations, the researchers could reconstruct the signaling network of the COPD lung. Macrophages emerged as dominant hubs, ranking at the top by both the number of interactions and the strength of the signals exchanged. In other words, the inflamed lung is not simply awash with generic inflammation; it is organized around macrophages and monocytes that coordinate the inflammatory conversation. This finding aligns with earlier single-cell work showing that immune and epithelial remodeling are central features of COPD pathology.

When the team turned to atherosclerotic plaques, they found a remarkably similar picture. The plaque microenvironment was immune-rich and dominated by myeloid cells, and communication networks again placed macrophages at the center of the signaling web, whether interactions were counted or weighted by strength. The parallel was striking: two organs, two diseases, and yet the same cellular architecture, with macrophage-centered inflammatory circuits at the core of both. This convergence suggested that the lung-artery connection might be written into the shared behavior of myeloid cells rather than being a byproduct of smoking or aging alone.

The next step was to find the molecular threads connecting these two networks. Comparing upregulated genes across matched immune cell populations in both diseases, the researchers identified a surprisingly short list of overlaps. In CD4-positive T cells, the shared genes included IFITM1, IGLC2, EIF1AY, NR4A1, and ZBTB16; in macrophages, HSPA1B and SIGLEC12; in monocytes, OLR1, PER1, and CH25H; and in natural killer cells, IFITM1, FKBP5, and HSPA1B. The restricted overlap is itself informative: although the two diseases share a similar immune framework, local tissue environments impose substantial transcriptional divergence. The genes that do persist across both settings, however, may represent conserved nodes of pulmonary and vascular inflammation.

To test whether these shared genes matter causally, the team turned to Mendelian randomization, a method that uses naturally occurring genetic variants as proxies to ask whether higher expression of a gene influences disease risk. They drew expression quantitative trait loci from the oneK1K resource, a large single-cell eQTL dataset of circulating immune cells, and paired them with genome-wide association statistics for COPD and coronary atherosclerosis from the FinnGen biobank. Because macrophage-specific eQTLs were unavailable, circulating monocyte subsets served as genetically accessible proxies for macrophage-related programs, a reasonable substitution given that monocytes recruited to inflamed tissues differentiate into macrophage-like cells.

The results were strikingly patterned. HSPA1B, which encodes a stress-inducible member of the HSP70 family of molecular chaperones, emerged as the only gene with robust associations across both diseases. Genetically predicted HSPA1B expression in classical monocytes, the CD14-dominant cells that flood sites of sustained inflammation, was positively associated with risk of both COPD and coronary atherosclerosis, with odds ratios of 1.119 and 1.154 respectively and extraordinarily narrow confidence intervals. Yet in non-classical monocytes, the CD16-dominant cells that patrol the endothelium and support vascular homeostasis, the association flipped: higher HSPA1B expression was linked to lower risk of both diseases. In NK cells, HSPA1B expression was positively associated with COPD risk. Sensitivity analyses using the MR-Egger intercept test found no marked directional pleiotropy, strengthening confidence in the signal.

This cell-state-dependent pattern may be the study’s most important insight. HSPA1B is a chaperone involved in proteostasis and cellular stress adaptation, and HSP70 pathways have long been implicated in inflammatory regulation. The new data suggest its role is not uniform across the myeloid compartment. In classical monocytes, which fuel cytokine production and generate inflammatory macrophages in both lung and plaque, higher HSPA1B may reflect or reinforce persistence within a pro-inflammatory environment. In non-classical monocytes, which perform endothelial surveillance and resolution-related functions, the same gene may instead participate in a homeostatic stress-response program. The same molecule, in other words, appears to mean different things depending on which myeloid state expresses it, a nuance that bulk-tissue studies would have completely missed.

The authors are careful to note the limitations of a computational and genetic study. The single-cell data came from distinct tissue environments, the genetic validation relied on circulating rather than lesion-resident cells, and residual linkage disequilibrium confounding at the HSPA1B locus cannot be excluded without formal colocalization analysis. Mechanistic experiments will be needed to show how HSPA1B actually regulates myeloid and NK-cell function. Even so, the study delivers a compelling model: COPD and coronary atherosclerosis are bound together by a shared macrophage- and monocyte-centered immune architecture, and HSPA1B stands out as a cell-type-specific signal at the intersection of pulmonary and vascular inflammation. If future work confirms the mechanism, targeting stress-response programs in specific myeloid states could one day treat both diseases at once.

Subject of Research: Cell-type-specific genetic and single-cell analysis of shared immune mechanisms linking COPD and atherosclerosis

Article Title: Cell‐Type‐Specific HSPA1B Expression Links COPD and Atherosclerosis

Article References: Zhao, Y., Cao, F., Zhang, H., Liang, Y., & Wu, Y. (2026). Cell‐Type‐Specific HSPA1B Expression Links COPD and Atherosclerosis. Immunity, Inflammation and Disease, 14(9), Article e70530. https://doi.org/10.1002/iid3.70530

Image Credits: AI Generated

DOI: 10.1002/iid3.70530

Keywords: COPD, atherosclerosis, HSPA1B, macrophages, monocytes, Mendelian randomization, single-cell RNA sequencing, HSP70, inflammation, NK cells, myeloid cells, comorbidity

The research team, led by Su-Hyeon Lee and Deok-Gie Kim, with corresponding authors Byungjin Hwang and Dong Jin Joo, took an unusually rigorous approach to a difficult clinical problem. They recruited 20 liver transplant recipients and collected paired samples of peripheral blood mononuclear cells, the circulating immune cells that include lymphocytes and monocytes, both before surgery and after transplantation. Ten of these patients went on to develop acute rejection and ten did not. Crucially, the two groups were matched for a battery of clinical variables that could otherwise confound the analysis, including age, sex, hepatocellular carcinoma status, autoimmune disease status, ABO blood group compatibility, and donor age. By controlling for these factors, the investigators could be more confident that the immunological differences they found were genuinely linked to rejection rather than to incidental patient characteristics.

Technically, the study is a tour de force of single-cell multi-omics. Rather than averaging gene expression across bulk tissue, the team used single-cell RNA sequencing to profile 88,940 high-quality individual cells, preserving the identity and state of each immune cell. They paired this transcriptomic readout with T cell receptor sequencing, which reads the unique genetic rearrangements that give each T cell its antigen-specific receptor. This combination allowed them to track not only which cell types were present and what genes they were expressing, but also how T cell clones expanded, contracted, and diversified over time. On top of the sequencing data, the researchers layered computational analyses of gene regulatory networks and intercellular communication, reconstructing the signaling conversations between immune cell populations that precede and accompany rejection.

The most striking finding is that the immune systems of future rejecters looked different before transplantation. Patients who later developed acute rejection already showed a distinct pre-transplant immune state compared with those who tolerated their new livers. Natural killer cells in the rejection group displayed an inflammatory activation profile with enhanced responsiveness to interferon, a family of signaling proteins central to antiviral and immune defense responses. Monocytes, the innate immune cells that patrol the blood and seed tissues, showed altered composition and transcriptional programs dominated by interferon-associated signatures. Together, these observations suggest a systemic, low-grade inflammatory readiness in the circulation of patients whose immune systems would later turn against the graft.

The adaptive immune side of the story was equally revealing. Before surgery, recipients who went on to reject showed a skewing of their CD8 T cell compartment toward effector memory states. Effector memory CD8 T cells are the rapid-response soldiers of the immune system: they circulate in the blood and peripheral tissues, and when they encounter their target antigen they can immediately deploy cytotoxic machinery without the delay required for naive T cells to differentiate. A pre-existing bias toward this compartment means the patient carries a standing army of cytotoxic cells primed for fast action, a configuration that could plausibly accelerate an attack on donor tissue once transplantation delivers a flood of foreign antigens.

After transplantation, the divergence between the two groups did not close; it widened in specific ways. Despite receiving standard immunosuppression, rejection patients maintained heightened overall immune activity. The team observed an expansion of KIR-expressing effector memory CD8 T cell populations in these patients. KIR, or killer cell immunoglobulin-like receptors, are molecules classically associated with natural killer cells that tune their reactivity to self, but their expression on CD8 T cells marks a subset with distinctive effector properties. The rejection group also showed increased expression of IRF1, a transcription factor that sits downstream of interferon signaling and orchestrates inflammatory gene programs in CD8 T cells. In other words, the post-transplant immune landscape of rejecters retained an activated, interferon-driven character that immunosuppression failed to fully extinguish.

To move from descriptive biology toward clinical utility, the researchers searched for genes whose expression reliably distinguished rejecting from non-rejecting patients across multiple time points. They identified 15 robust acute rejection-associated genes that were consistently detected before and after transplantation, and then validated a subset of these genes in liver biopsy tissue from the patients. This cross-validation is important: it links the circulating blood signature to the actual immunological battleground inside the graft, supporting the idea that a peripheral blood test could serve as a proxy for processes occurring in the transplanted liver. A blood-based biomarker panel built on such genes could, in principle, flag high-risk patients before rejection becomes clinically manifest, allowing clinicians to intensify monitoring or tailor immunosuppressive regimens without resorting to repeated biopsies.

The implications reach beyond liver transplantation. Acute cellular rejection is fundamentally a problem of immune recognition and memory, and the Yonsei study demonstrates that the relevant information is encoded in the composition and activation state of circulating immune cells. The finding that pre-transplant immune states predispose recipients to rejection challenges the traditional view of rejection as a purely post-transplant event driven by donor-recipient mismatch alone. Instead, the recipient’s baseline immune configuration, shaped by their disease history, viral exposures, and inflammatory milieu, appears to set the stage for how the immune system will respond to the graft. This reframing aligns with a broader trend in transplant immunology toward precision medicine, in which immunological risk stratification replaces one-size-fits-all immunosuppression.

There are, of course, important caveats. The study involved 20 carefully matched patients, a sample size appropriate for discovery but too small to support immediate clinical deployment of a diagnostic test. The 15-gene signature and the cellular features identified will need validation in larger, independent, and ideally multi-center cohorts before they can inform treatment decisions. It also remains to be seen whether the signatures generalize across different donor types, immunosuppressive protocols, and causes of liver failure. Nonetheless, the methodological framework, integrating single-cell transcriptomics, T cell receptor repertoire tracking, regulatory network inference, and tissue validation, provides a template that other transplant programs can adopt to build the evidence base needed for clinical translation.

For patients awaiting a liver, the promise is tangible: a pre-operative blood draw that reveals whether their immune system is primed for conflict, and post-operative monitoring that catches rejection in its earliest molecular stages rather than after tissue damage has occurred. For the field of transplant immunology, the study adds a detailed cellular and molecular atlas of how rejection unfolds in the human circulation, from interferon-primed natural killer cells and interferon-signature monocytes to KIR-expressing effector memory CD8 T cells and IRF1-driven inflammatory programs. As single-cell sequencing becomes faster and cheaper, the vision of routine immune profiling before and after organ transplantation moves closer to reality, and with it the possibility of preventing rejection rather than merely treating it.

Subject of Research: Single-cell RNA sequencing and T cell receptor repertoire analysis of immune signatures associated with acute liver allograft rejection

Article Title: Integrative single-cell RNA-seq and TCR repertoire analysis reveals distinct immunological features of acute liver allograft rejection

Article References: Lee, S.-H., Kim, D.-G., Cho, Y., Min, E.-K., Lee, J. G., Kim, M. S., Park, S., Hwang, B., & Joo, D. J. (2026). Integrative single-cell RNA-seq and TCR repertoire analysis reveals distinct immunological features of acute liver allograft rejection. Genome Medicine. https://doi.org/10.1186/s13073-026-01753-4

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01753-4

Keywords: liver transplantation, acute rejection, single-cell RNA sequencing, T cell receptor repertoire, CD8 T cells, natural killer cells, monocytes, interferon signaling, IRF1, biomarkers, immunosuppression, Genome Medicine