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PubMed2026

Influenza as a Less Commonly Recognized Cause of Hemophagocytic Lymphohistiocytosis: A Systematic Review of Case Reports and Case Series.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory condition that can be triggered by viral infections. However, influenza is not commonly recognized as a cause of HLH, and there is no comprehensive synthesis of influenza-associated HLH in the literature to guide clinicians. We conducted a systematic search of Pubmed and Embase to identify case reports and case series on influenza-associated HLH, and included 29 articles involving 47 patients. Their age ranged from 2 months to 72 years. 67% were males. Influenza A accounted for 91.3% of the cases, predominantly H1N1 (90.2%). All patients had fever, 60% had anemia, 69.7% had thrombocytopenia, 46.6% had leukopenia, 61.3% had splenomegaly, 71.4% had hypertriglyceridemia, and 94.7% had elevated ferritin levels. 97.6% had hemophagocytosis on biopsy. Antiviral therapy was administered in 89.5% of patients. HLH-directed therapy included corticosteroids (77%), intravenous immunoglobulin (36%), and etoposide (23.1%). Intensive care was required in 95.2% of cases. Overall survival was 53.2%. Survival rate was 50% among patients who received either antiviral therapy alone or HLH-directed therapy alone, compared with 65.4% among those who received both. Further studies are necessary to establish standardized diagnostic and therapeutic protocols for influenza-associated HLH.

Humans↗
PubMed2026

A Letter Matters: ADRB2 rs1042713 c.46A Modulates Anti-osteogenic Effect of Epinephrine in Human Mesenchymal Stem Cells.

Osteoporosis (OP) is a systemic bone disease affecting millions worldwide, characterized by long-term asymptomatic development that manifests in low-energy fractures. Due to their high stability, genetic markers represent a promising strategy for early diagnostics. The ADRB2 rs1042713 polymorphism is one such marker, considered as a potential predictor for OP. Although the anti-osteogenic role of the β2-adrenergic receptor is well-established, debate continues on which allele (G or A) of this polymorphism drives bone deterioration. In this study, we examined the influence of the ADRB2 rs1042713 G/G and A/A variants on osteogenic differentiation in patient-derived mesenchymal stem cells (MSCs) under treatment with the endogenous agonist epinephrine. We show that epinephrine (whose levels are often elevated in comorbid conditions) drastically impairs osteogenic differentiation, specifically at the matrix mineralization stage in MSCs A/A. Epinephrine fails to activate the canonical β2-adrenergic receptor pathway and promotes receptor perinuclear and nuclear localization in MSCs A/A. Crucially, metformin, a common anti-diabetic drug, rescues this anti-osteogenic effect. These results open new perspectives for early diagnostics by identifying epinephrine sensitivity as a critical factor, while also suggesting a potential therapeutic strategy to counteract epinephrine detrimental effect in individuals carrying the ADRB2 rs1042713 A-allele.

Humans↗
PubMed2026

Cryo-EM structure of TGFBIp fibrils driven by a corneal dystrophy-linked mutation enables design of peptide inhibitors of aggregation.

Corneal dystrophy is a heterogeneous group of diseases which manifests clinically by progressive corneal opacity and diminishing visual acuity. A group of corneal dystrophies are linked to autosomal dominant mutations in transforming growth factor β-induced protein (TGFBIp) and characterized by extracellular amyloid-positive deposits of unknown molecular structure. Here, we determined the cryogenic-electron microscopy (cryo-EM) structure of amyloid fibrils formed by the TGFBIp FAS1-4 domain with corneal dystrophy-linked mutation V624M. The L569 to N609 fibril core, which includes the Y571-R588 segment enriched in patient corneal deposits, forms symmetrical protofilaments with internal solvent channels. Leveraging this structure, we designed peptide inhibitors intended to bind onto fibril ends to block elongation, targeting the unequal growth of symmetrical protofilaments. Our G1 and H4 inhibitors exhibit concentration-dependent reduction of TGFBIp FAS1-4 aggregation as assessed by Thioflavin T, solubility fractionation, and electron microscopy. Our work illustrates how fibril structures can guide rational inhibitor design and suggests the targeting of protein aggregates as a therapeutic approach for corneal and ocular diseases.

betaIG-H3 Protein↗
PubMed2026

A case report of Xp21 contiguous gene deletion syndrome with adrenal crisis and sensorineural hearing loss: clinical highlights and management pitfalls.

OBJECTIVES: To report a rare association of Xp21 contiguous gene deletion syndrome (CGDS) featuring sensorineural hearing loss (SNHL), and to discuss the diagnostic and therapeutic challenges. CASE PRESENTATION: A male infant presented with a salt-wasting adrenal crisis consistent with X-linked adrenal hypoplasia congenita. His follow-up clinical course during childhood revealed global developmental delay and SNHL, the latter of which has been under-reported in the literature for this condition. At five years of age, the development of progressive proximal muscle weakness and markedly elevated creatine phosphokinase levels led to a diagnosis of Duchenne muscular dystrophy (DMD). The patient also exhibited pseudohypertriglyceridemia and elevated urinary glycerol, consistent with glycerol kinase deficiency. While initial exome sequencing failed to detect the genetic abnormality, subsequent chromosomal microarray analysis identified an Xp21 CGDS involving NR0B1, IL1RAPL1, DMD, and GK. Treatment of adrenal insufficiency with fludrocortisone and hydrocortisone was complicated by the higher steroid doses required for the management of DMD, resulting in exogenous Cushing syndrome and associated complications. CONCLUSIONS: This case highlights the necessity of evaluating for Xp21 CGDS in patients presenting with adrenal crisis and emphasizes the importance of multidisciplinary management to optimize outcomes in this complex pediatric endocrine disorder.

Humans↗
PubMed2026

A status update on the unkept promise of high-frequency spinal cord stimulation for treatment-refractory chronic migraine.

INTRODUCTION: Chronic migraine (CM) refractory to conventional pharmacotherapy (r-CM) remains a debilitating neurological condition with limited therapeutic options. High-frequency spinal cord stimulation at 10 kilohertz (HF-SCS) has recently emerged as a distinct neuromodulatory paradigm for this patient population. Unlike traditional spinal cord stimulation, HF-SCS operates above the frequency range that generates paresthesia, thereby eliminating stimulation-induced sensation while potentially engaging unique analgesic mechanisms. AREAS COVERED: This focused narrative review synthesizes the available clinical evidence, technical considerations, and mechanistic hypotheses specifically pertaining to cervical HF-SCS for refractory chronic migraine (r-CM). The authors further provide their expert perspectives on the future of this technology as a treatment option for refractory chronic migraine. EXPERT OPINION: Current data from prospective open-label studies and retrospective case series suggest that cervical HF-SCS may reduce monthly migraine days, facilitate conversion from chronic to episodic migraine patterns in some implanted patients, and may improve headache-related disability and quality of life over at least 52 weeks of follow-up. The paresthesia-free nature of HF-SCS confers a distinct advantage for both patient tolerability and future trial design, as it permits sham-controlled methodologies that have historically been impossible with conventional neurostimulation. However, these findings remain preliminary and should be considered hypothesis-generating pending confirmation in adequately powered randomized sham-controlled trials.

Humans↗
PubMed2026

Characterization of ZIC5 expression in esophageal squamous cell carcinoma and its association with patient survival.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy known for its aggressive nature and poor prognosis. The present study aimed to investigate the expression levels and clinical importance of the Zic family member 5 (ZIC5) gene in ESCC. Gene expression data and survival information obtained from The Cancer Genome Atlas and Gene Expression Omnibus were utilized. In 176 patients with surgically resected ESCC, immunohistochemical analysis was conducted to validate the expression of ZIC5 protein in cancerous and adjacent tissues. The findings of the present study revealed a significant upregulation of ZIC5 in ESCC compared with normal tissues (P<0.05), which was further corroborated by immunohistochemistry exhibiting a notable association between ZIC5 expression and clinical parameters such as tumor size, invasion depth, lymph node metastasis and TNM staging (P<0.05). Survival analysis further indicated that high ZIC5 expression was an independent prognostic factor for poor outcomes in patients with ESCC (hazard ratio=1.519; 95% CI: 1.017-2.269; P<0.05). In addition, bioinformatic analyses predicted that hsa-microRNA-212-5p may regulate ZIC5 mRNA and gene enrichment analysis suggested that ZIC5 may facilitate ESCC progression through involvement in the cell cycle and DNA repair pathways. In conclusion, ZIC5 is highly expressed in ESCC and associated with a poor prognosis, indicating its potential as a therapeutic target and biomarker for ESCC management. Further studies are warranted to elucidate the precise mechanisms underlying the role of ZIC5 in ESCC progression.

ESCC↗
PubMed2026

Tissue-derived extracellular matrix hydrogels instruct epigenetic adaptation in metastatic colonization.

The extracellular matrix (ECM) plays a central role in regulating tumor progression and metastatic colonization by providing biochemical and mechanical signals that shape cancer cell fate. However, most organoid culture systems rely on basement membrane extracts that fail to reproduce the tissue-specific extracellular environments encountered during metastasis. Here, we develop tissue-derived decellularized matrix hydrogels to reconstruct organ-specific microenvironments and investigate epigenetic adaptation to ECM cues during metastatic colonization. Patient-derived colorectal cancer organoids cultured in colon-derived matrices exhibited enhanced maintenance of stem-like phenotypes and colon-specific chromatin accessibility landscapes compared with cultures grown in basement membrane extracts, demonstrating improved physiological relevance for primary tumor modeling. When exposed to matrices derived from secondary organs, the organoids showed distinct growth phenotypes accompanied by rapid, tissue-dependent chromatin accessibility remodeling, indicating that ECM composition alone can reshape regulatory programs governing metastatic adaptation. Notably, liver-derived matrices selectively activated hepatocyte nuclear factor 4 alpha (HNF4A)-associated transcriptional networks and created a context-specific dependence on c-MET signaling for survival. Functional perturbation of HNF4A or c-MET signaling confirmed that both are required for organoid formation specifically within the liver matrix environment. Together, these findings establish tissue-derived matrix hydrogels as instructive bioactive materials that actively regulate cancer cell epigenetic states and reveal microenvironment-specific therapeutic vulnerabilities during early metastatic colonization.

Journal Article↗
PubMed2026

Mendelian randomisation for rheumatology: beyond hype-what it's good for, what it can't do, and how to read it critically.

Mendelian randomisation (MR) has become abundant in the literature, with variation in quality and frequent overinterpretation of causality. This creates a problem for clinical readers, reviewers, and editors: some MR studies can sharpen causal thinking, prioritise drug targets, and challenge misleading observational claims, whereas others are little more than automated exposure-outcome scans with causal claims disproportionate to the evidence. MR can strengthen causal inference when randomised trials are impractical and conventional observational studies are vulnerable to confounding, reverse causation, or selection bias. In rheumatology, credible MR can contribute to questions about disease aetiology, modifiable risk factors, therapeutic target validation, adverse-effect anticipation, and phenotype validation. However, its interpretation depends on whether the exposure is plausibly instrumentable, whether the genetic instruments are biologically defensible, whether assumptions are interrogated in ways appropriate to the design, and whether findings are triangulated with clinical, observational, experimental, and mechanistic evidence. Instead of recapitulating all methodological issues of MR, this review aims to help rheumatologists distinguish robust MR from weak or overinterpreted analyses quickly. We provide an accessible framework for reading and triaging MR studies in rheumatology. Papers that use poorly justified instruments, treat medication use as drug-target evidence, interpret genetic liability as diagnosis, rely on mechanical sensitivity analyses, ignore prior evidence or ask no clinically meaningful question can often be passed over by readers. The goal is not to discourage MR in rheumatology, but to raise the standard; useful MR should clarify causal reasoning rather than simply generate another statistically significant association.

Journal Article↗
PubMed2026

How the microbiome shapes epigenetic trained memory in neuroinflammation: Implications for neurodegenerative diseases.

Neurodegenerative diseases are increasingly recognized as disorders involving immune dysregulation. However, the mechanisms underlying this dysfunction remain poorly characterized. Trained immunity has recently emerged as a potential contributor to immune dysregulation, particularly in neuroinflammation and neurodegenerative diseases, where trained immunity is the epigenetic reprogramming of innate immune responses following an initial inflammatory stimulus, which increases responses to subsequent exposures. In parallel, although the brain has traditionally been viewed as an immune-privileged organ, growing evidence indicates that peripheral immune activity exerts significant influence on neuroinflammation in the brain. A major driver of peripheral immunity is the microbiome. Therefore, this perspective aims to present a conceptual framework for a relationship between the microbiome, trained immunity, and neurodegenerative diseases. We first summarize evidence of trained immunity in the brain and its role in neurodegeneration. Next, we highlight the role of the microbiome in peripheral immune modulation and in trained immunity. Finally, we propose potential mechanisms through which the microbiome may induce or modulate trained immunity in the brain. These include: 1) immunogenic microbial metabolites that cross the blood-brain barrier and alter host cell epigenetics; 2) migration of peripherally trained myeloid cells into the brain; 3) viral infection-induced trained immunity that may predispose to neurodegeneration. Together, this perspective suggests that microbiome-induced trained immunity offers a novel mechanism linking peripheral immune regulation with neuroinflammation and neurodegeneration with implications for therapeutic targeting of epigenetic modification as a molecular prevention strategy for progression of neurodegeneration.

Humans↗
PubMed2026

Venomous Lepidoptera: defensive toxin systems, venom composition, and clinical significance.

Venomous Lepidoptera constitute an underrecognized yet medically significant group of toxin-producing arthropods that employ contact-mediated defensive envenomation through specialized integumentary structures such as setae, spines, and scoli. Unlike actively stinging arthropods, these insects deliver venom passively upon contact, eliciting a diverse spectrum of clinical manifestations collectively termed lepidopterism. Clinical outcomes range from localized pain and dermatitis to severe systemic effects, including hemorrhagic syndromes, complement activation, and chronic inflammatory disorders. Recent advances in proteomic and transcriptomic technologies have transformed our understanding of lepidopteran venoms, revealing unexpectedly complex toxin repertoires comprising serine proteases, phospholipases, pore-forming proteins, disulfide-rich peptides, neuroactive RF-amide peptides, and immune-modulating components. These findings have provided new insights into the molecular basis of toxicity, host-pathogen interactions, and the evolutionary diversification of venom systems within Lepidoptera. This review synthesizes current knowledge on the morphology of venom-delivery structures, venom composition, mechanisms of action, and associated clinical manifestations, while highlighting medically important taxa, particularly species of the genus Lonomia. The successful development of antivenom against Lonomia envenomation underscores the translational relevance of lepidopteran toxin research and its potential for therapeutic innovation. By integrating molecular, clinical, and evolutionary perspectives, this review repositions venomous Lepidoptera as a legitimate and important component of arthropod toxinology. Furthermore, it identifies critical methodological limitations and key knowledge gaps, providing a framework for future investigations aimed at advancing our understanding of toxin biology, immunopathology, and the development of novel biomedical applications.

Animals↗
PubMed2026

Mitophagy-mediated ferroptosis involved in 2,5-hexanedione-induced neurotoxicity in rats.

n-Hexane, a widespread environmental and industrial pollutant, poses serious health risks, particularly neurotoxicity. Chronic exposure primarily induces sensorimotor neuropathy via its metabolite 2,5-hexanedione (HD), yet the mechanisms underlying HD-induced neuronal injury remain unclear. Recent evidence implicates ferroptosis, an iron-dependent form of regulated cell death, in neurodegenerative processes. In this study, Sprague-Dawley (SD) rats were exposed to HD to establish a neuropathy model. Ferroptosis involvement was assessed using the iron chelator deferoxamine (DFO) and the ferroptosis inhibitor Ferrostatin-1. The potential role of mitophagy in HD-induced ferroptosis was evaluated by monitoring mitophagy markers and by autophagy inhibition with chloroquine (CQ). In vitro, SH-SY5Y cells were transfected with PINK-1 siRNA to explore mitophagy-mediated regulation of ferroptosis. HD exposure led to iron accumulation, lipid peroxidation, mitochondrial abnormalities, and decreased GPX4 in rat spinal neurons. DFO or ferrostatin-1 treatment ameliorated these changes and preserved mitochondrial integrity. Mechanistic analyses revealed HD-induced activation of mitophagy, as shown by upregulation of Beclin-1, LC3II, Drp-1, and PINK-1, with concomitant downregulation of P62 in spinal mitochondria. CQ suppressed mitophagy, reduced iron deposition and lipid peroxidation, and improved motor function. Similarly, PINK-1 knockdown in SH-SY5Y cells mitigated HD-induced mitophagy and ferroptosis. These findings demonstrate that HD induces neuronal ferroptosis via mitophagy activation. Inhibition of ferroptosis or mitophagy effectively attenuates HD-induced neurotoxicity, suggesting potential therapeutic strategies to reduce neural damage from environmental n-hexane exposure.

Animals↗
PubMed2026

Efficacy and safety of JAK inhibitors for vitiligo: an updated systematic review and meta-analysis of randomized controlled trials.

Purpose: Janus kinase (JAK) inhibitors are a promising therapeutic option for vitiligo, but previous meta-analyses have focused mainly on topical ruxolitinib versus placebo. Newer randomized controlled trials (RCTs) evaluating oral agents and head-to-head comparisons with active treatments have not been comprehensively synthesized. Materials and methods: We searched PubMed, Embase, the Cochrane Library, and Web of Science to 11 March 2026. Eligible RCTs evaluated JAK inhibitor monotherapy versus placebo or active comparators. Two reviewers screened records, extracted data, and assessed risk of bias using RoB 2.0. The primary outcome was F-VASI75. Meta-analyses used fixed-effect or random-effects models. GRADE assessed certainty of evidence. Results: Nine RCTs (1826 patients) were included. JAK inhibitors increased F-VASI75 versus placebo (RR 4.59, 95% CI 3.20-6.59; p&#xa0;<&#xa0;0.001). For F-VASI50, they were superior to tacrolimus (RR 1.88, 95% CI 1.02-3.45) but not significantly different from dexamethasone (RR 2.17, 95% CI 0.95-4.94). Serious adverse events were comparable between groups (RR 1.15, 95% CI 0.57-2.33). Evidence certainty was moderate. Conclusions: JAK inhibitors are effective and well tolerated for vitiligo. Topical ruxolitinib is supported as a first-line option for limited facial disease; oral agents show promise but require longer-term safety data.

Humans↗
PubMed2026

HRAS promotes mutant NRAS-driven transformation with codon and allele specificity.

Wild-type RAS family members determine the signaling and therapeutic response in cancers driven by mutant HRAS and KRAS because they activate alternate RAS effector pathways. Here, we found that the requirement for wild-type RAS to support mutant NRAS-driven transformation correlated with codon-specific differences in GTP hydrolysis. NRAS with mutations at either Gly12 (G12X) or Gly13 (G13X), which retained the GDP-GTP cycling function, had modest autonomous transforming potential. In contrast, NRAS with GTP-locking mutations at Gln61 (Q61X mutants) was uncoupled from receptor tyrosine kinase (RTK) input, rendering wild-type RAS an obligate partner for RTK-stimulated signaling and oncogenesis. In RASless cells expressing mutant NRAS, reintroduction of wild-type HRAS was sufficient to restore signaling and transformation. Global dependency mapping in human cancer cells revealed functional partitioning, wherein mutant NRAS promoted MAPK signaling and wild-type HRAS promoted PI3K-AKT survival signaling. Consequently, allele-specific or pan-RAS(ON) inhibitors synergized with inhibitors of proximal RTK signaling or of wild-type HRAS or KRAS to overcome this signaling plasticity. Pan-RAS(ON) and HRAS inhibition was synergistic for all NRAS mutants tested, with Q61X mutants showing greater sensitivity. These findings define the signaling partnership between mutant NRAS and wild-type HRAS as a targetable vulnerability and provide a biochemical blueprint for dual RAS inhibition in NRAS-mutated malignancies.

Humans↗
PubMed2026

An Update on Inborn Errors of V(D)J Recombination.

V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte-specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical nonhomologous end joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEIs), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase [RAG1, RAG2, and the recently identified RAG cochaperone NudC domain-containing 3 (NUDCD3)], end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development.

Humans↗
PubMed2026

In vitro evaluation of sacituzumab govitecan in non-small cell lung cancer with actionable genomic alterations.

PURPOSE: The TROP2-directed antibody-drug conjugate sacituzumab govitecan (SG) has shown substantial therapeutic benefit in several malignancies; however, preclinical evidence supporting its activity in non-small cell lung cancer (NSCLC) is rare. MATERIALS AND METHODS: We evaluated 16 NSCLC cell lines harboring actionable genomic alterations for TROP2 expression and treated them with SG or its unconjugated payload, SN-38, for 3 days to determine cytotoxic effects. Apoptosis and DNA damage signaling were assessed using flow cytometry and western blot. SG internalization and lysosomal trafficking were visualized by confocal microscopy. RESULTS: SG had greater cytotoxic potency than SN-38, across all NSCLC cell lines, independent of genomic subtype or TROP2 expression level. Cell lines that were sensitive to SN-38 showed enhanced vulnerability to SG (P < 0.0001). Higher SLFN11 expression, a recognized determinant of SN-38 responsiveness, correlated with lower SG IC50 values. Both SG and SN-38 triggered apoptotic and DNA damage responses within 6-48 h, with SG inducing stronger activation of these pathways than SN-38. SG was efficiently taken up in CUTO17 and SNU-3173 adenocarcinoma cells, with more than 60% of the conjugate internalized within 3 h and subsequently localized to lysosomes. CONCLUSION: Our study provides in vitro evidence supporting the potential activity of SG in NSCLC with actionable genomic alterations. The efficacy of SG closely paralleled intrinsic sensitivity to the SN-38 payload, suggesting that DNA-damage responses, rather than oncogenic drivers, predominantly contribute to SG activity.

Actionable genomic alterations↗
PubMed2026

Policy pathways and historical insights: Canada's evolving approach to psychedelic access for end-of-life distress.

Canada's evolving attitudes toward psychedelic interventions in palliative and end-of-life care reflect a departure from historically prohibitionist policies and an emerging recognition of their therapeutic potential for individuals facing end-of-life distress. This shift parallels international regulatory developments in jurisdictions such as the United States, Australia and parts of Europe, where cautious policy liberalization has signaled growing acceptance of psychedelics within clinical contexts. Canada is also a relevant case because of its formative role in the development of modern palliative care, its contemporary frameworks emphasizing holistic approaches to suffering at the end of life, and its experience with medical assistance in dying, all of which have shaped national conversations about suffering, autonomy, and end-of-life care. Additionally, Canada's distinctive historical approach to drug regulation-marked by federal flexibility, mechanisms for compassionate access, and responsiveness to patient advocacy-combined with rising public demand and incremental provincial changes, may uniquely position the country along a transitional pathway toward clinical integration of psychedelics in palliative care. At the same time, Canadian drug policy remains heterogeneous across substances and provinces, underscoring the political contingency of reform. Within this dynamic landscape, Canada's psychedelic drug policy trajectory aligns with broader international trends toward cautious medicalization and regulated access to psychedelic therapies, while also offering an instructive case for how end-of-life frameworks and federal-provincial governance shape policy development.

Humans↗
PubMed2026

Decoding tumor immune microenvironment heterogeneity by single-cell and spatial multi-omics: From immunotherapy resistance to translational biomarkers.

Immune checkpoint blockade has transformed cancer therapy, yet primary and acquired resistance remain major clinical challenges. Increasing evidence indicates that immunotherapy resistance cannot be fully explained by tumor-intrinsic alterations or conventional biomarkers such as PD-L1 expression, tumor mutational burden, or microsatellite instability. Instead, therapeutic response is shaped by the tumor immune microenvironment (TIME) as a heterogeneous, spatially organized, and dynamically evolving ecosystem. Single-cell omics has revealed diverse immune and stromal cell states, including progenitor and terminally exhausted T cells, suppressive myeloid programs, B-cell/TLS-associated immune-reactive states, and CAF-mediated exclusion phenotypes. Spatial transcriptomics, spatial proteomics, and imaging-based approaches further demonstrate that these cell states assemble into distinct immune niches, including immune-inflamed, T-cell-excluded, myeloid-suppressive, metabolic/hypoxic, and TLS-associated niches. These spatial ecosystems determine whether antitumor immune cells can access malignant cells, receive antigen-presenting support, or become restrained by stromal, vascular, metabolic, and myeloid barriers. In this review, we summarize how single-cell and spatial multi-omics redefine TIME heterogeneity in immunotherapy resistance, highlight ligand-receptor communication networks linking cell states to spatial immune dysfunction, and discuss emerging translational biomarkers for patient stratification. We further propose that future immunotherapy biomarkers should evolve from static single-marker assays toward longitudinal, spatially resolved, and interpretable multi-omics models that guide precision combination immunotherapy.

Humans↗
PubMed2026

Weight Loss without Food Intake Suppression through Size-Dependent Retention of Anti-Inflammatory Nanomedicines.

Obesity is a risk factor for high-mortality health conditions, including cardiovascular diseases and type 2 diabetes, which makes the advancement of efficacious and safe weight loss therapies a high priority in pharmacology. The causal link between obesity and its comorbid conditions is believed to be a chronic state of inflammation originating within adipose tissue, with macrophages playing central roles, an axis that is not targeted directly by current therapies. Here, we use nanocarriers to deliver an anti-inflammatory glucocorticoid receptor agonist to adipose tissue macrophages and report the impact of size on therapeutic effect. Three dextran nanocarriers between 4-30 nm in hydrodynamic diameter released molecular drug cargo at equivalent rates and exhibited similar biological potency in vitro. In vivo in a mouse model of obesity, body weight and body fat were reduced in a size-dependent manner after 2-4 weeks of treatment. Unlike current clinical pharmacotherapies for weight loss, these body composition changes were not associated with changes in food intake. Greater retention of larger dextran nanocarriers in visceral adipose tissue appears to elicit a local change to promote browning by increasing mitochondrial abundance and lipid droplet fragmentation. Further development of this platform may result in a safe and potent modulator of adipose tissue in the state of obesity without direct action on nutrient intake to address malnutrition and lean body mass deficiencies observed with current weight loss pharmacotherapies.

Animals↗