Extreme temperatures are now recognized as significant global health threats, driving morbidity and mortality across diverse diseases by compromising epithelial barrier integrity and causing periepithelial inflammation. The epithelial barrier theory posits that environmentally induced barrier dysfunction, driven by modern industrial and urban exposures, leads to compromised surfaces of the exposed tissues accompanied by epithelial activation and barrier dysfunction, microbial dysbiosis, loss of commensal bacteria, opportunistic pathogen colonization, bacterial translocation, inflammation and immune dysregulation. While toxic chemical exposures have been the primary focus of barrier research, temperature extremes-now intensified by anthropogenic warming, altered weather patterns and regional climatic variability-may similarly disrupt epithelial structure and function. Heat and cold can alter tight-junction regulation, induce mitochondrial and endoplasmic reticulum stress, oxidative stress, apoptosis and modify cytokine and chemokine profiles, thereby weakening barrier defenses and enhancing susceptibility to pollutants, allergens and pathogens. These effects may be amplified by co-exposures such as humidity fluctuations, UV radiation, wildfire smoke and increased pollutant loads associated with floods, droughts and other environmental catastrophes. Shifts in the exposome, including contamination of water systems and food chains, further link temperature-related barrier injury to rising rates of noncommunicable diseases (NCDs). Clinical and epidemiological evidence supports associations between heat waves and disease exacerbations, between cold exposure and infectious or allergic responses, and between altered weather patterns and growing prevalence of NCDs. This review synthesizes mechanistic, environmental and epidemiological data to highlight extreme temperatures as critical drivers of epithelial barrier dysfunction and global disease burden.

Advanced prostate cancer is commonly described as immunologically cold, yet that label obscures a disease continually remodelled by treatment. Androgen-receptor (AR) pathway inhibition, chemotherapy, DNA-damage-directed therapy and radioligand treatment select resistant clones while altering lineage identity, metabolic dependence, antigen presentation and metastatic niches. AR-high, AR-low, double-negative, amphicrine and treatment-emergent neuroendocrine phenotypes are therefore better viewed as evolving immunometabolic states than as fixed histologies. Here, we develop a lineage-metabolism-immunity framework that integrates metastatic biopsies, longitudinal sampling, single-cell and spatial analyses, functional imaging and mechanistic prostate cancer models. Lineage determines which metabolic programmes remain available; tumour, stromal and immune cells then compete for nutrients and exchange metabolites that shape antigen presentation, myeloid suppression and lymphocyte function. We focus on glucose and lactate, lipids, amino acids, hypoxia-adenosine signalling and epigenetically active metabolites, while separating patient evidence from causal prostate cancer models and pan-cancer inference. The framework reframes three clinical tasks: identifying the state driving progression, recognising transitions under therapy and selecting combinations that relieve the dominant immune bottleneck without disabling effector cells. Translation will require longitudinal, lesion-aware measurements that connect lineage markers to functional evidence of metabolic dependence and immune context. The goal is not a universal metabolic target, but a tractable intervention matched to the tumour state, metastatic site and therapeutic window.

Among the most damaging anticipated consequences of climate change are rising global temperatures that are expected to exceed the heat tolerance of many species worldwide. Species' heat tolerance reflects adaptation to their historical environments, and rapid increases in ambient temperatures create a mismatch between evolved thermal tolerance and present-day heat exposures. This mismatch has severe implications because high temperatures can disrupt physiological processes across levels of biological organization. The immune system, specifically, may be particularly susceptible to dysregulation under climate warming because it is highly responsive to temperature. Although a rich body of empirical and clinical research has characterized the effects of heat on immunity, these findings are rarely interpreted in the context of evolved heat tolerance. Here, we provide a framework for predicting the immunological consequences of climate change by integrating results derived from five decades of immune research with evolutionary principles of heat tolerance. This framework offers a strong foundation for predicting the health and disease consequences of immune vulnerability to heat in a rapidly warming world.

Temperature extremes linked to climate change are becoming more frequent and more intense. This has significant implications for human health, including conditions driven by immune dysregulation. There is growing evidence that external thermal stress, particularly heat, may influence both the development and clinical course of several autoimmune conditions. Heat and cold can alter immune cell function through effects on cell signalling, cytokine production, barrier integrity and stress response within tissues. These mechanisms provide a strong biological basis for the observed associations between seasonal or regional temperature patterns and rates of autoimmune disease onset, symptoms, or flare frequency. Temperature extremes present considerable specific health risk to people with autoimmune disease with examples including heat waves worsening fatigue and neurological symptoms in people with multiple sclerosis and cold spells triggering blood vessel constriction and extremity tissue necrosis in systemic sclerosis. As climate instability increases, people with autoimmune disease will face higher clinical risk, due to disease-related factors and increased risks from cardiovascular related morbidity and mortality and concomitant demographic and socio-economic factors. This highlights the need for climate-aware healthcare, patient education, and research that addresses the interface of environmental factors with immune and clinical outcomes.

The thymus is a central regulator of immune competence, sustaining the continuous generation of a diverse and self-tolerant T-cell repertoire throughout life. Although traditionally regarded as primarily relevant during early development, accumulating evidence highlights its persistent role in shaping adaptive immunity across physiological and pathological conditions. In this review, we examine the role of thymic function as a determinant of immune competence and treatment efficacy across conditions in which adaptive immunity is challenged or therapeutically reshaped, including hematopoietic cell transplantation, severe infections, autoimmune diseases, immune checkpoint inhibitor therapy, and aging. In these contexts, impaired thymic activity is consistently associated with contraction of the naïve T‑cell pool, reduced T‑cell receptor (TCR) diversity, increased susceptibility to immune‑related complications, and inferior clinical outcomes. We then provide a critical overview of the methodologies currently available to assess thymic function, including flow-cytometric identification of recent thymic emigrants, molecular quantification of T‑cell receptor excision circles, analysis of TCR repertoire diversity, and imaging‑based approaches, highlighting their respective strengths, limitations, and translational applicability. Finally, we discuss the emerging relevance of thymic function in the context of adaptive and T‑cell-redirecting therapies, where sustained immune competence depends on the integrity of endogenous T‑cell regeneration. Collectively, this review positions thymic function as a clinically actionable biomarker for immune monitoring, patient stratification, and personalization of adaptive immunotherapies.

Extreme temperatures are emerging as major climate-sensitive drivers of chronic cardiovascular disease (CVD). Global warming has increased the frequency, duration, and intensity of heatwaves, while substantial cold-related risk persists, particularly in poorly insulated and socioeconomically vulnerable settings. Together, non-optimal temperatures account for millions of deaths annually, with a large and growing share attributable to CVD. In this narrative review, we synthesize epidemiological, mechanistic, and systems-level evidence linking heat and cold exposure to chronic cardiovascular outcomes, with a focus on ischemic heart disease, stroke, heart failure, and arrhythmias. We first outline key temperature metrics, shifting climate patterns, and challenges in exposure assessment, including the roles of humidity, diurnal variability, and indoor versus outdoor environments. We then summarize the epidemiology of temperature, CVD associations across diverse regions, highlighting U- and J-shaped exposure-response curves and disproportionate impacts in low- and middle-income countries, older adults, and socioeconomically disadvantaged communities. Mechanistic sections examine how heat and cold drive autonomic imbalance, endothelial dysfunction, oxidative stress, inflammation, haemoconcentration, changes in coagulation, renal injury, and myocardial oxygen supply-demand mismatch. We further discuss modifying effects of air pollution, wildfires, dust storms, and medication use, including clinically relevant drug-heat interactions in patients with chronic CVD. Finally, we review heat-health and cold-health action plans, health-system resilience frameworks, and emerging research gaps spanning exposure science, mechanistic studies, vulnerable populations, and policy evaluation. Recognising non-optimal temperature exposure as a modifiable environmental risk factor for chronic CVD is essential. Integrating climate-informed prevention, clinical care, and adaptation strategies offers substantial and timely opportunities to reduce cardiovascular burden in a warming and increasingly unstable climate.

Group B Streptococci (GBS) are both natural colonizers and important invasive pathogens in newborns. The introduction of intrapartum antibiotic prophylaxis has led to a significant decrease in the incidence of early onset sepsis. In contrast, late onset sepsis, which accounts for up to 50% of cases, has not declined. IAP impacts microbiome development during infancy, specifically it reduces the abundance of Bifidobacterium and Bacteroides spp., which might be associated with long-term health outcomes such as asthma development and obesity. This review highlights the challenges and risks associated with GBS colonization in neonates, including the role of virulence factors and specific contribution of host immunity. Bacterial pathogenicity factors involved in adhesion and colonization, e.g. GBS pilus islands, barrier disruption, e.g. pore-forming toxin β-hemolysin, or evasion of neonatal immune defense mediated by GBS capsular polysaccharide and membrane glycolipids are important targets to suppress the translocation of GBS and progression to invasive disease. In line with this, metabolic programming of neonatal immune cells, e.g. glycolytic capacity, is GBS strain-specific which also argues for a more tailored strategy of prevention. Given the benefits and risks of IAP, it is important to rethink strategies of preventing GBS disease including alternative strategies such as vaccination and probiotic supplementation. Further studies need to focus on modulating the developing immune-microbiome interplay including the metabolic milieu to the advantage of the vulnerable newborn.

The gut is increasingly recognized as a central immunological organ that orchestrates host immune responses and modulates distant mucosal sites, particularly the respiratory tract. In critical illness, disruption of intestinal barrier integrity and microbial homeostasis facilitates the translocation of bacteria, endotoxins, and metabolites into the systemic circulation, thereby contributing to the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The "gut-lung axis" has emerged as a key mechanistic framework linking intestinal dysfunction with pulmonary inflammation and immune dysregulation. Both direct and indirect effects of the gut microbiota play pivotal roles in shaping host immunity. Microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, regulate immune cell differentiation and function, particularly influencing the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells, which are critically involved in lung inflammatory responses. In addition, immune cells originating from the gut and bone marrow contribute to pulmonary immune activity, highlighting the systemic nature of gut-derived immune modulation. Conversely, alterations in lung microbiota can impact intestinal homeostasis, supporting the concept of bidirectional communication within the gut-lung axis. In this review, we comprehensively examine the pathophysiological mechanisms underlying ALI/ARDS across diverse etiological contexts from the perspective of gut-lung interactions, with a focus on immune cell dynamics and microbiota-derived metabolites. We further discuss emerging therapeutic strategies targeting the gut-lung axis, including microbiota modulation, fecal microbiota transplantation, and metabolic interventions. Elucidating these interconnected pathways may provide novel insights into the prevention and treatment of ALI/ARDS and advance the development of integrated organ support strategies in critical care medicine.

Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by immune dysregulation, microvascular injury, and progressive fibrosis. Among the immune populations implicated in SSc, macrophages are increasingly recognized as context-dependent participants in endothelial stress, inflammatory amplification, tissue remodeling, and fibroblast activation. Rather than relying on a static M1/M2 framework, recent studies support the view that macrophage-associated states are shaped by inducing cues, tissue niche, dominant effector function, and disease phase. In this review, we synthesize current evidence on macrophage-associated programs across vascular, dermal, and pulmonary compartments in SSc and discuss how these programs may help organize current understanding of the coupling between autoimmunity, vasculopathy, and fibrosis. We also highlight that recurrent signaling hubs-including JAK/STAT, TGF-β/SMAD, PDGF/PI3K/AKT/mTOR, Notch/Wnt, Hippo/YAP/TAZ, and metabolic regulators-reappear across macrophage-stromal crosstalk in SSc and related fibrotic settings. Importantly, we distinguish findings supported directly in human SSc from those derived from experimental systems or extrapolated from related fibrotic and autoimmune diseases, and we discuss biomarkers and therapeutic strategies according to their translational maturity. We propose that a macrophage-centered framework may be useful as an organizing and hypothesis-refining tool in SSc, but not as a validated disease-specific taxonomy or treatment algorithm. At present, many macrophage-centered biomarkers and therapeutic concepts remain insufficiently validated for routine clinical use, underscoring the need for stronger human tissue validation, clearer evidence calibration, and stage-aware translational studies.

Kidney fibrosis is the histopathological endpoint of chronic kidney disease, yet antifibrotic trials targeting individual molecular nodes have repeatedly failed to translate into patient benefit. The pattern suggests that renal fibrosis is sustained by a recurrent circuit rather than a linear cascade. Here we propose a tubular-macrophage lactate-lactylation circuit that integrates tubular and macrophage evidence into a single cellular axis. Injured tubular cells reprogramme glycolytically and generate a sustained lactate-rich niche. On both sides of the tubulointerstitial interface, lactate is converted into histone and non-histone lactyl-lysine (Kla) marks that lock in profibrotic transcription, derange mitochondrial function and dampen innate immune surveillance. Macrophage outputs, profibrotic macrophage programmes, innate-immune memory, paracrine activation of fibroblasts/pericytes and, in selected contexts, macrophage-to-myofibroblast transition, feed back on tubular cells and the stromal compartment through bidirectional vesicular and cytokine signalling, generating the recurrent topology that distinguishes a circuit from a linear pathway. The supporting evidence is uneven across compartments; we stratify each key claim by tier of evidence and map the circuit onto current biomarker and therapeutic strategies. The framework clarifies why single-node interventions have not succeeded, and points to combinations that engage substrate supply, lactylation machinery, transcriptional output and intercellular feedback in parallel.

Asthma is a heterogeneous chronic respiratory syndrome driven by complex interactions between environmental triggers and the host immune system while biologic therapies targeting downstream type 2 cytokines (e.g., anti-IL-5, anti-IL-4Rα) have improved outcomes, the recent success of upstream epithelial-targeting agents like Tezepelumab highlights the potential of targeting disease at its source. Accordingly, recent conceptual advances have redefined the airway epithelium from a passive structural shield to an active immunometabolic hub. This review provides a concise synthesis of emerging mechanistic insights into how airway epithelial cells (AECs) orchestrate both innate and adaptive immune responses. We systematically map the bidirectional crosstalk between the epithelium and diverse immune populations, highlighting how metabolic reprogramming, vesicle-mediated intercellular communication, and neuro-immune circuitry act synergistically to sustain chronic airway inflammation. Furthermore, we explore how these dynamic networks dictate distinct asthma endotypes, ranging from classic type 2 to non-type 2 phenotypes. By delineating these underlying pathobiological mechanisms, this article underscores the translational potential of targeting upstream epithelial signaling. Ultimately, advancing our understanding of this epithelial-immune interface paves the way for emerging precision therapeutics aimed at modifying disease progression and restoring airway homeostasis.

Programmed cell death protein 1 (PD-1) has long been considered a central molecule in CD8[+] T cell exhaustion and immunosuppression. However, recent studies have revealed that PD-1[+]CD8[+] T cells are not a homogeneous population of terminally dysfunctional cells, but rather constitute key immune cells with significant heterogeneity and functional plasticity within tissue immune microenvironments. PD-1 signaling operates throughout multiple stages of CD8[+] T cell biology, including thymic development, peripheral activation, chronic antigen stimulation, and tissue residency. By finely regulating T cell receptors (TCRs) signal strength, metabolic state, and transcriptional programs, it deeply participates in cell fate decisions while limiting immunopathology. In chronic infections and tumors, persistent antigen stimulation drives PD-1[+]CD8[+] T cells to form an exhaustion lineage with a defined differentiation hierarchy, encompassing stem-like precursor cells, effector-like transitional cells, and terminally exhausted cells. PD-1 is not only a characteristic marker of this lineage but also a critical regulatory node through which immune checkpoint blockade therapy exerts its therapeutic effects. Furthermore, in contexts such as tissue-resident memory T cells (TRM), GZMK[+]CD8[+] T cells, and other disease-associated microenvironments, sustained PD-1 expression often represents an adaptive functional regulatory state rather than mere functional inhibition. This review explores the multidimensional regulatory roles of PD-1 in CD8[+] T cells, with a focus on elucidating the diverse functions and clinical significance of PD-1[+]CD8[+] T cells in cancer, chronic infections, and autoimmune diseases.

Adenomyosis is a common and difficult disease in gynecology. Its main clinical manifestations include uterine hypertrophy, excessive menstruation, pelvic pain and infertility, which have a serious impact on women's health. Seriously affects women's health. At present, the pathogenesis of this disease is not clear; however, the increase in local estrogen and the occurrence of an inflammatory response are widely believed to be closely related to the development of adenomyotic lesions. Although progress has been made in understanding how estrogen and inflammation play their respective roles in adenomyosis, the relationship between estrogen and inflammation and its impact on adenomyosis are not fully understood. In this work, we summarize the effects of estrogen and inflammation on the occurrence and development of adenomyosis, including the involved biological processes and related signal transduction mechanisms, as well as the targeted drugs for clinical treatment, and further summarize the interactions between the two in adenomyosis as well as the available evidence for clinical applications. This review helps to broaden our understanding of the role of the vicious inflammatory‒estrogen cycle in the pathogenesis and pathophysiology of adenomyosis, and it provides new ideas for the treatment of uterine adenomyosis.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with a complex pathophysiological mechanism and a marked sex difference in prevalence and disease severity, with women being more affected and showing a more aggressive disease course. Recent studies indicate that a complex interplay among gut microbiota (GM), their metabolites, and sex hormones is a crucial factor in AD pathogenesis. In this review, we attempted to synthesize current studies to critically discuss the tripartite interplay among GM, sex hormones, and the brain in AD. Firstly, we discuss the role of the microbiota-gut-brain axis in AD pathogenesis with a focus on how gut dysbiosis contributes to neuroinflammation, disruption of the blood-brain barrier (BBB), and accumulation of pathological proteins. Then, we discuss the mechanistic roles of various GM-derived metabolites in AD pathogenesis, with a focus on the two-edged role of SCFAs and their derivatives, the neuroactive role of tryptophan and its derivatives, and the modulatory roles of bile acids and trimethylamine N-oxide. Finally, we discuss a novel concept, the "microgenderome," referring to the bidirectional interplay between sex hormones and GM, and how GM regulates sex hormone levels through unique enzymatic functions termed the "estrobolome" and a newly proposed "testobolome."