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.
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.
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.
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.
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.
