Functional State Research Articles

Diversity and function of regulatory T cells in health and autoimmune diseases.

Regulatory T cell (Treg) play a pivotal role in immune regulation and maintaining host immune homeostasis. Treg heterogeneity, characterized by diverse gene expression profiles and functional states, is complex in both health and disease. Research reveals that Tregs are not a uniform population but exhibit diversity based on their origin, location, and functional status. This heterogeneity is crucial for understanding Treg roles in various pathological conditions. Dysfunctional Tregs are closely linked to the pathogenesis of autoimmune diseases, although the precise mechanisms remain unclear. The phenotypic and functional heterogeneity of Tregs is particularly significant in diseases such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, psoriasis and autoimmune liver diseases. This review explores Treg origins, classifications, and heterogeneity in these conditions, aiming to provide new perspectives and strategies for diagnosis and treatment. Understanding Treg heterogeneity and plasticity promises to reveal novel therapeutic targets and advance precision immunotherapy development.

Transdiagnostic white matter controllability deficits across patients with affective and anxiety spectrum disorders

BackgroundAffective and anxiety disorders including major depression disorder (MDD), post-traumatic stress disorder (PTSD), and social anxiety disorder (SAD) are characterized by network dysconnectivity. Network controllability quantifies the capability of specific brain regions to impact functional dynamics based on the underlying structural connectome. This study aimed to investigate transdiagnostic and illness-specific network controllability alterations across these three disorders. Materials and methodsThe study enrolled 233 currently untreated and non-comorbid subjects, including 68 MDD patients, 51 PTSD patients, 46 SAD patients, and 68 healthy controls (HCs). White matter network controllability was compared among the four groups, and its associations with symptom severity and duration of untreated illness were evaluated. ResultsCompared with HCs, patients with PTSD, MDD and SAD exhibited reduced average controllability in the somatomotor, subcortical, and default mode network, notably in brain regions such as the superior frontal gyrus, postcentral gyrus, paracentral gyrus, pallidum, posterior cingulate, and putamen. MDD and SAD patients exhibited reduced average controllability in the left lateral occipital gyrus and bilateral accumbens. SAD patients showed reduced average controllability in the dorsal attention network. These controllability changes did not correlate with illness duration or symptom severity. LimitationsThe cross-sectional design limits causal inference, and adjusting for age and sex differences may not completely eliminate their influence on the results. ConclusionThe present study revealed shared and specific alterations of network controllability in MDD, PTSD, and SAD, suggesting reduced ability of specific brain regions/networks in driving the brain system into different functional states across these disorders.

Brain state forecasting for precise brain stimulation: Current approaches and future perspectives.

Transcranial magnetic stimulation (TMS) has the potential to yield insights into cortical functions and improve the treatment of neurological and psychiatric conditions. However, its reliability is hindered by a low reproducibility of results. Among other factors, such low reproducibility is due to structural and functional variability between individual brains. Informing stimulation protocols with individual neuroimaging data could mitigate this issue, ensuring accurate targeting of structural brain areas and functional brain states in a subject-by-subject fashion. However, this process poses a set of theoretical and technical challenges. We focus on the problem of online functional targeting, which requires collecting electroencephalography (EEG) data, extracting brain states, and using them to trigger TMS in real time. This stream of operations introduces hardware and software delays in the real time set-up, such that brain states of interest may vanish before TMS delivery. To compensate for delays, it is necessary to process the EEG signal in real time, forecast it, and instruct TMS devices to target forecasted - rather than measured - brain states. Recently, this approach has been adopted successfully in a number of studies, opening interesting opportunities for personalised brain stimulation treatments. However, little has been done to explore and overcome the limitations of current forecasting methods. After reviewing the state of the art in brain state-dependent stimulation, we will discuss two broad classes of forecasting methods and their suitability for application to EEG time series. Subsequently, we will review the evidence in favour of data-driven forecasting and discuss its potential contributions to TMS methodology and the scientific understanding of brain dynamics, highlighting the transformative potential of big open datasets.

The reaction mechanisms of ethylene oxide and propylene oxide with food Simulants: Based on experiments and computational analysis.

Ethylene oxide (EO) and propylene oxide (PO) are widely used as sterilizing agents in the food industry. However, their residues in food packaging can migrate into food and react with it, affecting the accuracy of residue detection in food. This study aims to explore the reaction mechanisms between EO and PO and aqueous food simulants using both experimental and computational methods. Especially to investigate the effects of temperature, pH and material structure on these reactions. Experimentally, the stability of EO and PO in different types of aqueous food simulants at 20°C, 40°C and 70°C was observed. It was found that at 20°C, EO and PO reacted rapidly in 4% EtOH, which 90% has reacted in 72h, and only 10%-20% reacted in other types of food simulants. All reactions accelerated with increasing temperature. At 70°C, all reactions have been completed except for 50% EtOH, which 80% has reacted in 72h. Gas chromatography-mass spectrometry (GC-MS) analysis revealed that EO and PO can form diols or glycol ethers. Computationally, Density Functional Theory (DFT) and Transition State Theory (TST) was used to calculate the energy barriers of the reaction processes. The results showed that the energy barrier for the reaction of EO and PO with water is about 125kJ/mol. The energy barrier can be reduced by about 40kJ/mol with acid catalysis. Reactivity at the binding sites was analyzed through the Fukui function (FF), average local ionization energy (ALIE), and electrostatic potential (ESP) analysis. According to the results, the f+value at C7 in PO is 0.041 higher than it at C5. The ESP value of EO is 0.15kcal/mol higher than that of PO and the ALIE value of EO is also 0.11eV higher. The experimental results show the impact of temperature, and calculation results highlight the effects of pH and material structure on reaction mechanism. These results can help guide the development of safer packaging materials and provide theoretical support for more accurate detection of residues in food.

Spatiotemporal Forecasting of Functionality States of Community Building Portfolios under Flood Evolution

Spatiotemporal Forecasting of Functionality States of Community Building Portfolios under Flood Evolution

Coupling of mitochondrial state with active zone plasticity in early brain aging

Neurodegenerative diseases typically emerge after an extended prodromal period, underscoring the critical importance of initiating interventions during the early stages of brain aging to enhance later resilience. Changes in presynaptic active zone proteins ("PreScale") are considered a dynamic, resilience-enhancing form of plasticity in the process of early, still reversible aging of the Drosophila brain. Aging, however, triggers significant changes not only of synapses but also mitochondria. While the two organelles are spaced in close proximity, likely reflecting a direct functional coupling in regard to ATP and Ca2+ homeostasis, the exact modes of coupling in the aging process remain to understood.We here show that genetic manipulations of mitochondrial functional status, which alters brain oxidative phosphorylation, ATP levels, or the production of reactive oxygen species (ROS), can bidirectionally regulate PreScale during early Drosophila brain aging. Conversely, genetic mimicry of PreScale resulted in decreased oxidative phosphorylation and ATP production, potentially due to reduced mitochondrial calcium (Ca2+) import.Our findings indicate the existence of a positive feedback loop where mitochondrial functional state and PreScale are reciprocally coupled to optimize protection during the early stages of brain aging.

МОРФОФУНКЦИОНАЛЬНЫЕ И БИОЭЛЕКТРИЧЕСКИЕ ХАРАКТЕРИСТИКИ НЕКОТОРЫХ МЫШЦ ЗАПЯСТНОГО СУСТАВА У СОБАКИ: ПИЛОТНОЕ ИССЛЕДОВАНИЕ

The paper presents the morphofunctional characteristics of some muscles of the dog's wrist joint, as well as their bioelectrical characteristics. The purpose of the study is to describe the bioelectrical characteristics of the radial and ulnar extensor carpi of the dog, taking into account the morphofunctional characteristics of these muscles. Objectives of the study: to conduct a morphological and electrophysiological study of the radial and ulnar extensor wrist muscles in dogs; identify patterns of EMG formation depending on the internal structure and innervation of muscles, and conduct a comparative assessment of the morphological and bioelectrical characteristics of the muscles being studied. Research was carried out at the Department of Anatomy, Histology, Physiology and Pathological Anatomy of the Omsk State Agrarian University named after P.A. Stolypin (Omsk). As a result of the studies, it was revealed that the innervation of the muscle fibers of the dog’s extensor carpi ulnaris and radialis has a similar, group character, that is, groups of muscle fibers have a large number of motor units. These groups are reflected on the EMG as separate complexes. An individual set of action potentials in the EMG signal pattern has duration of 0.01–0.014 s and a frequency of 600–800 Hz. The length of the muscle bundles inboth muscles is different: for the extensor carpi ulnaris it is 0.5 cm, for the radial one, respectively, 3.5 cm. Thus, it was found that the characteristics of the innervation and internal structure of the muscle affect the pattern of the EMG signal. The influence of muscle structure by the type of feathering and the length of muscle fibers (in feathery muscles) was not revealed. Thus, the resulting pattern (pattern) of the EMG signal is characteristic of statodynamic muscles. The proposed model of EMG signal formation, as a result of further development, will have the prospect of being used for qualitative and quantitative interpretation and assessment of the functional state of the neuromuscular system in animals and humans.

A multi-domain feature fusion epilepsy seizure detection method based on spike matching and PLV functional networks.

The identification of spikes, as a typical characteristic wave of epilepsy, is crucial for diagnosing and locating the epileptogenic region. The traditional seizure detection methods lack spike features and have low sample richness. This paper proposes a seizure detection method with spike-based phase locking value (PLV) functional brain networks and multi-domain fused features. 

Approach. In the spiking detection part, brain functional networks based on PLV are constructed to explore the changes in brain functional states during spiking discharge, from the perspective of microscopic neuronal activity to macroscopic brain region interactions. Then, in the epilepsy seizure detection task, multi-domain fused feature sequences are constructed using time-domain, frequency-domain, inter-channel correlation, and the spike detection features. Finally, Bi-LSTM and Transformer encoders and their optimized models are used to verify the effectiveness of the proposed method. 

Main results. Experimental results achieve the best seizure detection metrics on Bi-LSTM Attention, with accuracy, sensitivity, and specificity reaching 98.40%, 98.94%, and 97.86%, respectively. 

Significance. The method is significant as it innovatively applies multi channel spike network features to seizure detection. It can potentially improve the diagnosis and location of the epileptogenic region by accurately detecting seizures through the identification of spikes, which is a crucial characteristic wave of epilepsy.

Mental health of volunteers: origin of psychosomatic disorders in PTSD conditions

Background. Numerous studies in various scientific areas deal with to the problem of mental health of Ukrainians: the theory and practice of psychological and pedagogical research, psychophysiological concepts and theories, a systematic approach in psychology, the psychophysiological aspect of the emotional background, as well as psychosomatic features of optimal personality functioning. Preservation of mental health has become a priority of the state policy of Ukraine to support the country’s stability and fighting capacity. The study of the impact of psychoemotional factors on the functional state of the body for the restoration and optimization of life support among volunteers who provide free psychological assistance and support the mental health of the population is relevant. The research was aimed at studying the origin of psychosomatic disorders in volunteers with post-traumatic stress disorder (PTSD), as well as determining the impact of these disorders on their mental health and psychosocial status. Materials and methods. The following psychodiagnostic tools were used: emotional burnout diagnosis method according to V. Boyko, NEWS questionnaire, PCL-5 questionnaire and post-traumatic growth questionnaire. According to the results of the study, it was found that emotional burnout in volunteers manifests itself in three phases: tension, resistance, and exhaustion according to indicators of a high level of stress and severe depression in respondents with signs of PTSD (23.9 %). Results. Mental disorders such as asthenic, anxiety-phobic, hysteroform and depressive syndromes are observed in all groups. Conclusions. The psychosomatic mechanism of the relationship between mental activity and behavior in PTSD includes the influence of a traumatic psycho-emotional factor that causes a constant feeling of danger, panic attacks or fear of repeating the situation, a feeling of hopelessness, low mood, apathy, loss of interest in usual activities, aggression, irritability, frequent conflicts and anger outbursts, feelings of detachment, social isolation, relationship problems and guilt for experiencing PTSD symptoms.

Multiplexed spatial mapping of chromatin features, transcriptome and proteins in tissues.

The phenotypic and functional states of cells are modulated by a complex interactive molecular hierarchy of multiple omics layers, involving the genome, epigenome, transcriptome, proteome and metabolome. Spatial omics approaches have enabled the study of these layers in tissue context but are often limited to one or two modalities, offering an incomplete view of cellular identity. Here we present spatial-Mux-seq, a multimodal spatial technology that allows simultaneous profiling of five different modalities: two histone modifications, chromatin accessibility, whole transcriptome and a panel of proteins at tissue scale and cellular level in a spatially resolved manner. We applied this technology to mouse embryos and mouse brains, generating detailed multimodal tissue maps that identified more cell types and states compared to unimodal data. This analysis uncovered spatiotemporal relationships among histone modifications, chromatin accessibility, gene expression and protein levels during neuron differentiation, and revealed a radial glia niche with spatially dynamic epigenetic signals. Collectively, the spatial multi-omics approach heralds a new era for characterizing tissue and cellular heterogeneity that single-modality studies alone could not reveal.

Novel transcripts of EMT driving the malignant transformation of oral submucous fibrosis

Oral submucous fibrosis (OSF) is a chronic, progressive, and fibrotic condition of the oral mucosa that carries an elevated risk of malignant transformation. We aimed to identify and validate novel genes associated with the regulation of epithelial-to-mesenchymal transition (EMT) in OSF. Genes regulating EMT were identified through differential gene expression analysis, using a LogFC threshold of -1 and + 1 and a padj value < 0.05, based on data from GEO datasets and the TCGA-HNSC datasets. The curated EMT genes were correlated with functional cancer states and subjected to clustering to identify candidate genes. Integration of bioinformatics and proteomics led to the discovery of the EMT genes MMP9, SPARC, and ITGA5 as novel candidates. Comprehensive pathway and immunohistochemical analyses confirmed their roles in regulating EMT in OSF, oral squamous cell carcinoma (OSCC), and OSF-associated squamous cell carcinoma (OSFSCC). The significant roles of MMP9, SPARC, and ITGA5 in fibrosis and malignancy suggest a novel mechanism in which fibrosis-associated type 2 EMT undergoes transition to type 3 EMT, driving OSF towards malignancy.

Efficiency of surgical treatment for complicated cataract: clinical and functional analysis

Background. Despite the successes of ophthalmic surgery, the treatment of complicated cataract remains challenging due to concomitant conditions such as lens subluxation and glaucoma. The purpose of the study was to assess the clinical and functional state of the eye in patients with complicated cataract after lens extraction. Materials and methods. The study involved 54 patients: 36 with uncomplicated cataract (controls) and 18 (main group) with cataract complicated by primary open-angle glaucoma (POAG). They underwent an ophthalmic examination, including visometry, tonometry, echobiometry, and ophthalmoscopy. The examination was performed before surgery, the next day, 1, 3 and 6 months after phacoemulsification. Results. Six months after surgery, 97.23 % of controls and 94.45 % of patients in the main group had visual acuity ≥ 0.5. On the first day after phacoemulsification, the mean intraocular pressure (IOP) increased by 3.14 ± 0.15 mm Hg in the control group and by 0.84 ± 0.02 mm Hg in patients with POAG, but by the end of the follow-up, there was a decrease in IOP in 50 and 44.5 % of cases, respectively, compared to preope­rative values. One month after surgery, the anterior chamber depth increased by 0.94 mm in controls and by 0.44 mm in patients of the main group, remaining stable until the end of the follow-up. Conclusions. Clinical follow-up of patients with uncomplicated cataract and cataract complicated by POAG showed that after phacoemulsification, there was an improvement in visual function, stabilization of IOP and an increase in the anterior chamber depth. An increase in IOP on the first day after surgery is transient, and the dynamics of indicators over 6 months confirms the effectiveness of surgical intervention.

The diversity of natural killer cell functional and phenotypic states in cancer.

The role of natural killer (NK) cells as immune effectors is well established, as is their utility as immunotherapeutic agents against various cancers. However, NK cells' anti-cancer roles are suppressed in cancer patients by various immunomodulatory mechanisms which alter these cells' identity, function, and potential for immunosurveillance. This manifests in abnormal NK cell responses accompanied by changes in phenotypic or genotypic identity, giving rise to specific NK cell subsets that are either hypofunctional or, more broadly, defective in their responses. Anergy, senescence, and exhaustion are some of the terms that have been used to define and characterize these NK cell functional states. These responses vary not only with cancer type but also NK cell location within tissues. Collectively, these phenomena suggest a highly plastic nature of NK cell biology in tumors. In this review, we present and discuss a summary of these functionally distinct states and provide an overview of how NK cells behave at different locations within the context of cancer.

Improving brain health via the central executive network.

Cognitive and physical stress have significant effects on brain health, particularly through their influence on the central executive network (CEN). The CEN, which includes regions such as the dorsolateral prefrontal cortex, anterior cingulate cortex and inferior parietal lobe, is central to managing the demands of cognitively challenging motor tasks. Acute stress can temporarily reduce connectivity within the CEN, leading to impaired cognitive function and emotional states. However a rebound in these states often follows, driven by motivational signals through the mesocortical and mesolimbic pathways, which help sustain inhibitory control and task execution. Chronic exposure to physical and cognitive challenges leads to long-term improvements in CEN functionality. These changes are supported by neurochemical, structural and systemic adaptations, including mechanisms of tissue crosstalk. Myokines, adipokines, anti-inflammatory cytokines and gut-derived metabolites contribute to a biochemical environment that enhances neuroplasticity, reduces neuroinflammation and supports neurotransmitters such as serotonin and dopamine. These processes strengthen CEN connectivity, improve self-regulation and enable individuals to adopt and sustain health-optimizing behaviours. Long-term physical activity not only enhances inhibitory control but also reduces the risk of age-related cognitive decline and neurodegenerative diseases. This review highlights the role of progressive physical stress through exercise as a practical approach to strengthening the CEN and promoting brain health, offering a strategy to improve cognitive resilience and emotional well-being across the lifespan.

Psychophysiological reserves of the body as a basis for the formation of educational adaptation of higher education students

The article confirms the importance of studying the issue of forming the educational adaptation of students. It is shown that the functional indicators of the cardiovascular (adaptive potential of blood circulation) and nervous (level of situational and personal anxiety) systems are diagnostic markers of students' adaptation to the educational process. The assessment of psychophysiological reserves of the student’s organism (40 full-time students) was conducted on the basis of the Mykhailo Dragomanov Ukrainian State University. The anxiety level was carried out using the test of Ch.D. Spielberger - Yu.L. Khanin. The assessment of compensatory and adaptive mechanisms was carried out using the calculated criterion of the adaptive potential of the circulatory system (AP) proposed by R.M. Baievskyi. It is found that most first- and second-year students have a high level of anxiety, especially during the examination period, which is due to academic stress exacerbated by military events. Instead, the average group level of students' adaptive potential is satisfactory, characterized by sufficient functional capabilities of the body. The results of the study have identified the need for regular monitoring of the functional state of the cardiovascular and central nervous systems of first- and second-year students. It has been established that pedagogical measures aimed at improving the effectiveness of educational adaptation should include rationally organized physical activity. The importance of including the educational component “Physical Education” in the curriculum of training specialists regardless of specialty for 1st and 2nd year students in order to increase the functional capabilities of the body, prevent the development of chronic psycho-emotional stress, especially in martial law conditions, is substantiated.

Tissue-resident memory CD8 T cell diversity is spatiotemporally imprinted.

Tissue-resident memory CD8 T (TRM) cells provide protection from infection at barrier sites. In the small intestine, TRM cells are found in at least two distinct subpopulations: one with higher expression of effector molecules and another with greater memory potential1. However, the origins of this diversity remain unknown. Here we proposed that distinct tissue niches drive thephenotypic heterogeneityof TRM cells. To test this, we leveraged spatial transcriptomics of human samples, a mouse model of acute systemic viral infection and a newly established strategy for pooled optically encoded gene perturbations to profile the locations, interactions and transcriptomes of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. Our study reveals that the regionalized signalling of the intestinal architecture supports two distinct TRM cell states: differentiated TRM cells and progenitor-like TRM cells, located in the upper villus and lower villus, respectively. This diversity is mediated by distinct ligand-receptor activities, cytokine gradients and specialized cellular contacts. Blocking TGFβ or CXCL9 and CXCL10 sensing by antigen-specific CD8 T cells revealed a model consistent with anatomicallydelineated, early fate specification. Ultimately, our framework for the study of tissue immune networks reveals that T cell location and functional state are fundamentally intertwined.

OP23 Neutrophil Niches and Therapy Resistance in Ulcerative Colitis: Spatial Atlas Insights

Abstract Background Resistance to tumor necrosis factor inhibitor (TNFi) therapy remains a major obstacle in managing ulcerative colitis (UC), affecting up to 50% of patients.1 The complex interplay of immune cells and their spatial organization in the gut mucosa is poorly understood but likely contributes to therapeutic outcomes.1,2 This study utilized advanced multiplexed imaging to construct a spatial atlas of UC, providing insights into cellular interactions driving TNFi resistance. Novel spatial omic technologies show to be able to add additional thus far unknown insights to this question. Methods A total of 42 tissue regions from 29 UC patients and 5 healthy controls were analyzed using CODEX multiplexed imaging. Spatially resolved single-cell data, encompassing over 1.7 million cells, were used to identify distinct cell types and map cellular neighborhoods (CNs). Pairwise cell-cell contacts and CN-level functional states were analyzed in TNFi-treated and untreated patients, correlating findings with clinical outcomes. Results TNFi therapy led to normalization of adaptive immune CNs, such as lymphoid aggregates, with reductions in T-cell frequencies and associated contacts. However, innate immune CNs, including neutrophil-enriched granulocyte niches and inflamed stroma, remained unchanged despite treatment. Notably, neutrophil-dominated CNs exhibited persistent expression of pro-inflammatory markers, such as TNFR2 and CD137, implicating these niches in sustaining mucosal inflammation and therapy resistance. Additionally, sex-dependent differences were observed, with higher TNFi responsiveness in females potentially linked to adaptive immune modulation.3 Conclusion Neutrophil-dominated inflammatory niches represent a potential mechanism of TNFi resistance in UC.3,4 These findings highlight the importance of targeting innate immune pathways alongside TNFi therapy to improve outcomes. By integrating spatial insights with functional data, this study paves the way for precision medicine approaches in UC management.

Examination of the carbon monoxide diffusing capacity in children with oncohematological diseases after hematopoietic stem cell transplantation

The article presents the results of the study of the diffusion capacity of the lungs (DSL) for carbon monoxide by single inhalation (DLco) in children with acute leukemia (AL) and acquired idiopathic aplastic anemia (AIAA) after allogeneic hematopoietic stem cell transplantation (HSCT). A comparative analysis of the DLco indicator before the HSCT and on the 30th, 90th, 180th, 360th days after it was carried out. Its significant irreversible decrease was revealed starting from 30 days after HSCT during the year of follow-up in most patients with AL. In children with AIAA, a significant decrease in DSL was also registered after a month of follow-up, however, by a year of dynamic control, the changes were less pronounced than in AL group, and the average DLco value was restored to indicators before transplantation. This method is important to use in a comprehensive assessment of the functional state of the respiratory system for the timely diagnosis of pulmonary complications after HSCT.

Dynamic Neural Mechanisms Underlying Sustained Motor Training Post-Stroke: An fNIRS Investigation Employing Time-Varying ALFF and Functional Connectivity Analysis.

Motor dysfunction of the upper limbs following a stroke predominantly arises from abnormal motor patterning caused by the disrupted balance of inter-cortical communication within motor-associated cortical regions. Temporal analysis offers a more precise reflection of the cortical functional state in affected patients. This study employed fNIRS to capture hemodynamic responses among 20 stroke patients and 19 healthy controls in both resting and Baduanjin task state. Including computing the coefficient of variation of fractional amplitude of low-frequency fluctuations (fALFF) for each channel, alongside extracting dynamic state metrics. Findings indicate that, during sustained motor tasks, stroke patients exhibit a diminished fALFF variability in targeted cortical regions; these individuals display a higher prevalence of low-intensity states and a lower prevalence of high-intensity states during task execution. These dynamic state attributes are significantly associated with scores on the upper limb motor function scale (FMA-UE), thereby proposing a time-domain perspective for investigating the underlying mechanisms of stroke-induced motor dysfunction.

The Role of the Tumor Microenvironment in T-Cell Redirecting Therapies of Large B-Cell Lymphoma: Lessons Learned from CAR-T to Bispecific Antibodies.

T-cell redirecting therapies, which include chimeric antigen receptor T-cells (CAR-Ts) and bispecific antibodies (BSAs), have revolutionized the treatment of relapsed\refractory large B-cell lymphoma (LBCL). Expanding clinical experience with these advanced therapies shows the potential for the optimization of their use with combination or consolidation strategies, which necessitates the prognostic stratification of patients. While traditional clinical prognostic factors identified in the era of chemotherapy are characterized by limited value, the tumor microenvironment (TME) is becoming a new prognostic cluster. We examine how the heterogeneity of LBCL, characterized by variations in tumor parameters and differences in TME immune cell composition, immune checkpoint expression, and cytokine milieu, correlates with both positive responses and resistance to treatment. While classical parameters such as histological subtype, cell of origin, and target antigen expression lack proven prognostic value for T-cell redirecting therapies, the density and functional state of tumor-infiltrating lymphocytes, tumor-associated macrophages, and immune checkpoint molecules are shown to be critical determinants of therapeutic success, particularly in CAR-T therapy. We identify several gaps in the current knowledge and suggest that the insights gained from CAR-T experience could be instrumental in refining BSA applications. This report also highlights limitations in the current knowledge, as TME data derive from a limited number of registrational trials with varying methodologies, complicating cross-study comparisons and often focusing on immediate response metrics rather than long-term outcomes. By dissecting the complex interactions within the TME, this review aims to identify new prognostic factors and targets, ultimately fostering more effective and tailored treatment strategies for LBCL patients.