Aug 2026· Ageing Research Reviews· Vol 122, pp.
103342
· 0 citations· 292 references
Medicine
TL;DR
This review dissects the differential regulatory mechanisms of ICD-mediated immune memory in CNS tumors versus non-tumor diseases and aims to elucidate the molecular switches that govern the transition of this immune program from a beneficial, compensatory state to a pathological, detrimental phenotype.
Abstract
The central nervous system (CNS) harbors a distinct immune memory programming system, wherein immunogenic cell death (ICD) acts as a pivotal signaling hub. A spectrum of insults, from systemic metabolic dysfunction to local protein aggregation and ionic dyshomeostasis, can provoke ICD in neurons, glia, and resident immune cells. This process orchestrates the release of damage-associated molecular patterns (DAMPs) from distinct subcellular compartments. These DAMPs synergistically initiate both innate trained immunity (TI), characterized by profound metabolic-epigenetic reprogramming, and antigen-specific adaptive immune responses that traverse the blood-brain barrier. Together, these pathways constitute an integral network of central immune surveillance. Crucially, this ICD-driven immune programming exhibits a striking functional dichotomy depending on the pathological context. In non-neoplastic conditions such as neural injury and neurodegenerative diseases, uncontrolled ICD signaling can establish a pathological trained immune memory, driving a self-perpetuating cycle of chronic neuroinflammation and tissue damage. Conversely, within the tumor microenvironment of malignancies like glioma, the adaptive immune responses elicited by ICD are frequently subverted by potent immunosuppressive mechanisms, culminating in tumor immune escape. This review dissects the differential regulatory mechanisms of ICD-mediated immune memory in CNS tumors versus non-tumor diseases. We aim to elucidate the molecular switches that govern the transition of this immune program from a beneficial, compensatory state to a pathological, detrimental phenotype. By exploring emerging therapeutic strategies, including gene editing, nanomaterials, and bioactive phytochemicals that precisely target ICD pathways, we provide a theoretical framework for understanding CNS immune homeostasis and for the rational design of precision immunotherapies.
Background Immune escape remains a major barrier to durable benefit from immunotherapy in breast cancer, particularly in immune-cold tumors and those with an immune-excluded architecture. Emerging evidence from cancer neuroscience suggests that nerves are not passive bystanders of the tumor microenvironment, but active regulators of stromal remodeling, myeloid polarization, T-cell dysfunction, metastatic adaptation, and neuroendocrine stress biology. Main body We synthesize current evidence supporting a multiscale model of neuro–immune crosstalk in breast cancer. We first examine sympathetic innervation as an upstream coordinator of immunosuppressive signaling through β-adrenergic pathways that reshape myeloid compartments, lymphangiogenesis, and effector lymphocyte fitness. We then discuss sensory-nerve-driven immune exclusion, focusing on CGRP–CAF–ECM circuits and Substance P-associated inflammatory relays that stabilize prometastatic states. Next, we review direct nerve–tumor interfaces, including neurotransmitter-dependent synapse-like signaling, pseudo-synaptic coupling, extracellular-vesicle/TNT-mediated metabolic communication, and mitochondrial transfer, and evaluate their potential roles in immune resistance and metastatic competence. We further integrate these local interactions into a systems framework by considering tumor–brain–sympathetic feedback loops and neuroendocrine outputs that reset host immune thresholds while emphasizing the context-dependent nature of neural regulation across tumor types and microenvironmental states. Finally, we summarize neurodevelopmental programs co-opted during metastasis, discuss emerging technologies for neural phenotyping and spatial analysis, and highlight clinically actionable vulnerabilities, including β-blockade, CGRP-axis modulation, RET/TRK-targeted therapy, and phenotype-guided combination strategies. Conclusion This framework positions neural signaling as an upstream integrator of immune escape in breast cancer and suggests that neural biology may enable biologically informed stratification of immunotherapy-resistant tumors into distinct and targetable states.
Xingyu Li, Xu Gong, Yizi Cong et al.· Frontiers in Immunology· 0 citations
Central nervous system (CNS) disorders are fundamentally linked to metabolic dysregulation within immune and glial cells. This review provides a systematic synthesis of immunometabolic reprogramming-encompassing glucose, lipid, and amino acid metabolism, and oxidative phosphorylation-in CNS-resident microglia, immunomodulatory astrocytes, and peripherally infiltrating immune cells (T cells, B cells, and neutrophils) across Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Critically, rather than presenting all reported metabolic alterations as equivalently established, we introduce an evidence-transparency framework that systematically distinguishes the nature of supporting data-ranging from direct metabolic flux measurements (Seahorse, isotope tracing, lipidomics) and molecular correlates, to genetic/pharmacological perturbations, human tissue validation, and model-specific observations-enabling readers to independently assess the strength of each major conclusion. We further delineate aging as an active analytical dimension, demonstrating how age-related changes in mitochondrial quality control, lipid handling, redox buffering, and glial-immune crosstalk establish a permissive baseline that modifies disease-specific reprogramming trajectories. By integrating analyses of intercellular crosstalk, neuroinflammation, blood-brain barrier integrity, and oxidative stress, we illustrate both convergent and divergent metabolic mechanisms across diseases. Finally, we critically assess therapeutic strategies targeting immunometabolism, emphasizing shared translational obstacles including target selectivity, blood-brain barrier penetration, stage-dependent efficacy, and the inherent challenge of pathway pleiotropy. This review provides a conceptually grounded framework for interpreting immunometabolic evidence, navigating the gap between correlative findings and causal mechanisms, and guiding future hypothesis-driven therapeutic design for CNS disorders.
Nan Li, Yuanyuan Wu, Huiyi Feng et al.· Ageing Research Reviews· 0 citations
Abstract Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response, is characterized by a dynamic progression from hyperinflammation to immunosuppression. Its persistently high mortality underscores the limitations of therapies focused solely on immune homeostasis. This review advocates a paradigm shift that positions the nervous system as a central orchestrator of host defense through a hierarchical neuroimmune axis. This axis comprises three interconnected tiers: (1) peripheral effector pathways—the cholinergic anti-inflammatory pathway and the sympathetic-adrenal-medullary axis; (2) central integrative hubs in the brainstem (eg, nucleus tractus solitarius) and limbic system; and (3) molecular translators that convert neural signals into cellular immune responses. In sepsis, maladaptive plasticity within these circuits leads to a pathological “uncoupling” of immune sensing from neural control, driving organ dysfunction and perpetuating both runaway inflammation and subsequent immunosuppression. We critically evaluate emerging neuromodulation strategies—including bioelectronic vagus nerve stimulation, splenic focused ultrasound, precise electroacupuncture, and receptor-specific pharmacology—with careful distinction between established mechanistic evidence, preclinical findings, and early-stage clinical data. The future direction lies in precision neuromodulation, an evolving concept encompassing closed-loop systems responsive to dynamic biomarkers, chronotherapy, and targeted nanomedicine, though these approaches require substantial technical and clinical validation. This framework charts a roadmap for evolving sepsis management from supportive care toward proactive modulation of endogenous regulatory networks, while emphasizing that further mechanistic studies, biomarker validation, and well-designed clinical trials are essential prerequisites for clinical translation.
Chuntao Wang, Xiaojiang Huang, Chaoyao Hou et al.· Journal of Inflammation Rese...· 0 citations
The central nervous system (CNS) has long been considered immune privilege due to the blood-brain barrier, lack of traditional lymphatic drainage, and unique immune microenvironment. However, recent neuroimmunology research has demonstrated that the CNS maintains continuous communication with the peripheral immune system via meningeal lymphatic vessels, lymphoid systems, and border-associated macrophages. This paradigm shift has brought tertiary lymphoid structures (TLSs), ectopic lymphoid aggregates induced by chronic inflammation, infection, or tumors, into focus as key players in neuroimmune interactions. TLSs exert a dual effect in neuroinflammation. In infectious diseases like viral encephalitis, they promote local antibody production and T cell responses, aiding pathogen clearance. In contrast, in multiple sclerosis, autoimmune encephalitis, Alzheimer's disease, and Parkinson's disease, TLSs may sustain chronic inflammation, drive autoantibody production, and accelerate neurodegeneration. This review systematically summarizes the composition, induction mechanisms, and functional heterogeneity of TLSs across neurological diseases. We discuss their protective versus pathogenic roles in neuroinflammation and highlight their diagnostic value and therapeutic potential, aiming to provide new insights for precision intervention in neuroimmunological disorders.
Yan Zhang, Peishen Han, Xiaoling Zhang· Journal of Neuroinflammation· 0 citations
Cancer progression is profoundly influenced by the complex interplay between the tumor microenvironment (TME), the immune system, and the patient's psychological state. This review delineates a critical pathway linking chronic stress to worsened cancer outcomes through inflammatory factors, anti-tumor immune suppression, and the induction of behavioral comorbidities. We postulate that sustained stress hormone signaling via the sympathetic nervous system and hypothalamic-pituitary-adrenal axis activation orchestrates a systemic immunosuppressive cascade. A central mechanism is the stress-induced expansion and functional polarization of myeloid cells, including myeloid-derived suppressor cells, tumor-associated macrophages, and neutrophils within the TME. These cells foster a pro-tumoral milieu by impairing T-cell function, promoting angiogenesis, and facilitating metastasis, among other processes. Beyond the local TME, stress-mediated inflammation propagates to the central nervous system, compromising the blood-brain barrier and activating microglia. This neuroinflammatory response drives structural and functional remodeling in key brain regions such as the prefrontal cortex, hippocampus, and amygdala, providing a biological basis for depression and anxiety often seen in patients with cancer. This creates a vicious cycle wherein psychological distress exacerbates tumor-promoting inflammation and immune evasion, which in turn worsens behavioral symptoms. Critically, clinical evidence now links psychological stress to chemoresistance and poor responses to immunotherapy. We argue that integrating stress-reducing interventions and strategies targeting neuroinflammation into cancer care is not merely supportive but essential to disrupt this detrimental cycle. A multidisciplinary approach that concurrently targets the tumor, the immune system, and the patient's mental well-being holds the promise of improving both survival and quality of life.
Yadiel A. Rivera-López, Luinet L. Meléndez-Rodríguez, Orlando Torres-Rodriguez et al.· Brain, Behavior, & Immunity...· 0 citations
Inflammation is a fundamental component of immune defense but also a major driver of pathology across autoimmune, neurodegenerative, and trauma-associated diseases. Dysregulated inflammation propagates chronic tissue damage that current therapies fail to adequately control. Existing treatments rely on systemic immunosuppression or single-target biologics, which are limited by toxicity and insufficient tissue penetration. There is a critical need for tissue-targeted, dynamically controllable anti-inflammatory therapies.
We developed a multifunctional, programmable cell therapy platform that engineers regulatory T cells (Tregs) into living cellular pharmacies. These SMART Tregs are designed to home to disease-specific tissues, deliver anti-inflammatory disease-modifying molecules, and express biologics such as neuroprotective factors or functional enzyme replacements. We have established proof of concept for the platform in models of ALS and Alzheimer’s disease.
Preliminary studies demonstrate our engineered Tregs can persist within the central nervous system and maintain functional activity, supporting feasibility for neuroinflammatory and neurodegenerative indications. The platform introduces three key innovations: integration of immune regulation with localized delivery, disease-context activation, and the ability to secrete persistence factors to extend therapeutic activity. Ongoing studies will evaluate disease-modifying molecule activity, in vivo efficacy, and biodistribution.
This Treg platform represents a paradigm shift in cell therapy, enabling precision immune modulation and localized therapeutic delivery across multiple disease contexts. The approach offers significant translational potential to several indications, including mitigation of neuroinflammation, immune-mediated injury, and protein replacement. This technology provides a validated, scalable cellular therapy platform ready for preclinical transition and partnership with translational stakeholders.
This work was supported by grants from the National Institutes of Health (NS102556, NS117895, and NS132666), Department of Defense (AL230089), and funds from the Center for Synthetic Immunity, Geisel School of Medicine at Dartmouth.
Neuroimmunology (NEUR)
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