Characterization of the presence and evolution of clonal hematopoiesis (CH) in patients with unexplained cytopenias is fundamental to risk-stratifying patients and optimizing clinical surveillance for malignant progression. We investigated the mutational spectrum and clonal metrics in a cohort of 256 patients with chronic idiopathic neutropenia (CIN)-clinically overlapping with idiopathic cytopenia of undetermined significance with isolated neutropenia (ICUS-N)-and assessed clonal presence and dynamics through longitudinal tracking of 104 patients with a median follow-up of 32 months. CH was identified in 12.5% of patients, primarily involving single DNMT3A or TET2 mutations. Longitudinal analysis revealed two distinct mutational patterns: an age-related pattern, predominantly involving DNMT3A and TET2 single mutations, which showed marginal changes in clone size and associated with stable disease course, and a high-risk pattern, primarily driven by SRSF2 and IDH1/2 mutations, characterized by higher clonal expansion and a high risk of malignant progression. Malignant transformation in CIN was significantly associated with baseline variant allele frequency (VAF) (VAF > 10%), the presence of multiple mutations, and detection of specific driver mutations (SRSF2, IDH1/2). An annual VAF increase (ΔVAF/year) ≥7.5% was found to optimally predict evolution, thus showing that clonal dynamics can serve as an indicator of disease outcome. Longitudinal assessment of peripheral blood hematologic parameters was found not to display clinically significant changes. These findings provide important insight into high-risk evolutionary patterns in CIN and underscore the importance of longitudinal monitoring with next-generation sequencing (NGS) for clinical decision-making and risk-adapted management in CIN patients with clonal cytopenia.

Conventional CD8+ T cells can acquire natural killer (NK) cell receptors upon persistent antigen exposure, forming antigen-experienced NK-T (AENK-T) cells. Their dual-state plasticity within the tumor immune microenvironment determines cancer immunotherapy outcomes. This narrative review synthesizes recent transcriptomic, epigenomic, and functional data to define the trajectory, regulation, and therapeutic relevance of AENK-T cells. The analysis establishes a "temporal hierarchy" differentiating AENK-T cells from innate-like T cells: activating NK receptors (NKG2C, NKG2D) emerge early, while inhibitory receptors (NKG2A, killer-cell immunoglobulin-like receptors, KLRB1) accumulate under sustained stimulation. Mechanistically, BCL11B downregulation and the T-bet-Zeb2 axis stabilize a cytotoxic Effector AENK-T state. Conversely, the TOX-LAG-3 loop and SOX4-ID3 axis drive transition into a suppressive Exhausted AENK-T state, mirroring terminal exhaustion. The tumor immune microenvironment accelerates this shift via hypoxia, metabolic competition, and TGF-β, contrasting with chronic infection models. Translating these findings, an evaluation of emerging strategies, such as NKG2A blockade, biomarker-guided patient selection, and next-generation chimeric antigen receptor (CAR)-T cell engineering, suggests that temporally informed approaches targeting the AENK-T trajectory may overcome current immune checkpoint therapy limitations.

Primary malignant bone tumors may initially resemble common musculoskeletal conditions, creating uncertainty about when first-contact clinicians should escalate care. This narrative review integrates selected guidelines, diagnostic-pathway studies, and imaging and biopsy literature to translate established principles into practical decisions before specialist referral. We propose actionable diagnostic delay as a descriptive, unvalidated framework: the potentially avoidable interval between a documented clinical trigger for escalation and initiation of the corresponding action. It complements, rather than replaces, established patient, diagnostic, referral, and treatment intervals. Concerning symptom trajectories, examination findings, aggressive or indeterminate imaging, and clinical-imaging-pathology discordance guide reassessment, imaging, referral, or coordinated biopsy. Plain radiographs are the first imaging step; persistent clinical suspicion despite normal radiographs warrants MRI or specialist referral. Referral should not await MRI when access is limited. A 2-4-week reassessment window is proposed only for mild, stable, low-suspicion presentations with adequate radiographs showing no suspicious or indeterminate lesion and is not an evidence-validated waiting period. Suspected fracture or acute neurological compromise requires emergency assessment. Metastatic carcinoma and myeloma are considered in parallel in the appropriate clinical context, while solitary or atypical aggressive lesions require a sarcoma-safe diagnostic pathway. Contemporary biopsy evidence supports specialist planning and radiology-pathology correlation, but diagnostic accuracy varies with case mix and sampling. Associations between diagnostic intervals and survival remain inconsistent and vulnerable to confounding by tumor biology. The framework therefore prioritizes diagnostic and procedural safety rather than a presumed survival benefit. Its performance, referral burden, and applicability across healthcare systems require prospective evaluation.

Cuproptosis is a copper-dependent form of regulated cell death driven by copper binding to lipoylated tricarboxylic acid (TCA) cycle proteins. This interaction triggers aberrant protein aggregation, Fe-S cluster protein degradation, and mitochondrial proteotoxic stress, and its unique metabolic dependency distinguishes cuproptosis from apoptosis and ferroptosis. This review examines the bidirectional regulation between cuproptosis and anti-tumor immunity. Cuproptosis can promote dendritic cell maturation and CD8+ T cell-mediated immunity through immunogenic cell death (ICD), damage-associated molecular pattern release, and cGAS-STING pathway activation. Activated CD8+ T cells may in turn enhance tumor cell cuproptosis sensitivity via IFN-γ-STAT1-IRF1-driven FDX1 upregulation, forming a positive feedback loop. Conversely, direct copper toxicity toward T cells and NK cells, spatial heterogeneity of intratumoral copper distribution, and potential immunosuppressive cytokine release may counterbalance these immunostimulatory effects. We outline core controversies regarding the universality of cuproptosis immunogenicity, the immune activation window of copper ions, and the clinical utility of cuproptosis biomarkers. Translational strategies including copper ionophore-immunotherapy combinations, copper-based nano-delivery systems, and copper metabolism-based patient stratification are discussed. The cuproptosis-immunity intersection remains at an early stage; key mechanistic findings require independent validation before clinical translation.

In situ vaccination (ISV) is a local tumor-directed immunotherapy strategy that uses a treated tumor as an endogenous, patient-specific source of tumor antigens and a site of immune activation, with the goal of converting local treatment into systemic and durable antitumor immunity. Depending on the modality, ISV induces immunogenic cell death, other forms of tumor-cell stress or death, or local innate immune activation, thereby increasing antigen availability, promoting type I interferon signaling, and supporting dendritic cell-mediated cross-priming of tumor-reactive T cells capable of mediating both local and systemic antitumor immunity, including regression of untreated lesions. Across immunocompetent preclinical models, ISV can generate durable local tumor control, abscopal responses, and long-term immune memory, particularly when combined with modalities that amplify antigen release or inflammatory signaling. Early clinical studies employing intratumoral innate immune agonists, radiotherapy-based regimens, cytokines, and oncolytic viruses demonstrate clinical feasibility, favorable safety profiles, and emerging evidence of systemic efficacy in selected tumor types. In this review, we discuss the immunologic principles underlying ISV and organize the field according to major triggering modalities, including radiotherapy, ablation, and light-based therapies, selected chemotherapies, innate immune agonists, cytokines, and oncolytic viruses. We further highlight emerging intratumoral delivery platforms, such as lipid nanoparticles, injectable hydrogels, and biodegradable scaffolds, that enable precise spatial and temporal control of immune activation within the tumor microenvironment. Finally, we review the evidence that locally initiated antitumor immunity can extend beyond the treated lesion to control untreated lesions and metastatic disease, and discuss the challenges associated with achieving durable systemic efficacy and preventing recurrence.

Gastric cancer remains one of the leading causes of cancer-related death worldwide, with particularly high incidence in East Asia. Despite improvements in surgical resection and perioperative chemotherapy, patients with advanced or metastatic disease face a poor prognosis. The arrival of ICIs, especially anti-PD-1 antibodies such as nivolumab, has offered new treatment options. The landmark CheckMate 649 trial showed that adding nivolumab to chemotherapy significantly improves overall survival in advanced GC, gastroesophageal junction cancer, and esophageal adenocarcinoma. However, longer-term follow-up analyses have made it clear that a substantial proportion of patients either do not respond initially or relapse after an initial response. Thus, there is an urgent need to understand the mechanisms behind immunotherapy resistance.

Cancer cachexia is conventionally viewed as muscle wasting but is increasingly recognized as a tumor-driven immunometabolic syndrome. This systemic disorder is characterized by a vicious cycle of metabolic dysregulation, systemic inflammation, and immune evasion, severely compromising the efficacy of immune checkpoint inhibitors (ICIs). Conventional single-target therapies have largely failed to disrupt this redundant pathological network. Here, we comprehensively review the therapeutic potential of Traditional Chinese Medicine (TCM) as multi-target network modulators acting at the immunometabolic interface. At the micro-level, TCM-derived monomers (such as curcumin, andrographolide, and epigallocatechin gallate (EGCG)) bidirectionally target this interface by concurrently suppressing muscle catabolism (via ubiquitin-proteasome and ferroptosis pathways) and reprogramming the immunosuppressive tumor immune microenvironment (TIME) (downregulating PD-L1 and inhibiting MDSCs/Tregs). At the macro-level, chromatographically characterized multi-herb formulas offer systemic recalibration via the gut-muscle-immune axis, utilizing microbial metabolites to restore intestinal barrier integrity, curb systemic inflammation, and epigenetically reinvigorate exhausted CD8+ T cells. Clinically, integrating TCM with ICIs presents a promising synergistic strategy to restore patient eligibility, optimize immunotherapeutic responses, and mitigate treatment-related adverse events. This review provides a mechanistic framework for positioning TCM as a potential systemic adjuvant to break the cachexia-immunosuppression loop in modern oncology.

The prognostic relevance of baseline low-level viremia (LLV) after hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) diagnosis remains uncertain. We evaluated the association between baseline LLV and overall survival (OS), explored related biological features, and developed survival prediction models for patients with baseline LLV.

IL-2 is a pleiotropic cytokine that plays a central role in the activation and proliferation of cytotoxic lymphocytes and regulatory T cells. Since its discovery in 1976 as a T-cell growth factor and its subsequent U.S. FDA approval for metastatic renal cell carcinoma and melanoma, IL-2 has represented a landmark in cancer immunotherapy. However, high-dose (HD) IL-2 therapy is associated with substantial toxicities, including vascular leak syndrome. Recent advances in structural and receptor biology have clarified the molecular mechanisms underlying IL-2's dual immunostimulatory and immunoregulatory effects. These discoveries have enabled the design of next-generation IL-2 variants (IL-2v) with improved pharmacokinetics, receptor selectivity, and safety profiles. Importantly, PD-1+ TCF-1+ stem-like CD8+ T cells have recently been identified as a key population sustaining long-term antitumor immunity. TCF-1 is a transcription factor associated with a less differentiated, self-renewing state and marks this progenitor-exhausted subset. By contrast, terminally exhausted T cells exhibit a highly differentiated, poorly proliferative state and limited capacity for functional reinvigoration, whereas progenitor-exhausted cells retain stem-like properties, self-renewal capacity, and responsiveness to therapy. Furthermore, these cells respond robustly to IL-2 and are central mediators of the synergy observed between IL-2 signaling and PD-1 blockade. Mechanistically, PD-1 inhibition releases inhibitory constraints, while IL-2 provides a potent STAT5-driven proliferative and differentiation signal that expands the stem-like CD8+ T-cell pool and generates functional effector CD8+ T cells. This review summarizes IL-2 biology, the limitations of high-dose IL-2 (HD IL-2) therapy, and emerging strategies, including CD25- or CD122-biased IL-2 variants, tumor-targeted IL-2 prodrugs, and IL-2-based combination therapies designed to harness IL-2's antitumor potential while minimizing systemic toxicity, with particular emphasis on the role of stem-like CD8+ T cells as key mediators of therapeutic efficacy.

Myasthenia gravis (MG) is a heterogeneous neuroimmune disorder in which pathogenic autoantibodies impair neuromuscular junction transmission and produce fluctuating skeletal muscle weakness. Although conventional therapy with acetylcholinesterase inhibitors, corticosteroids, and broad immunosuppressants remains effective for many patients, its limitations are increasingly evident, including delayed onset, cumulative toxicity, and inadequate control in refractory disease. These challenges have accelerated the transition from non-selective immunosuppression to biologic and other targeted therapies. Recent advances in MG have revealed that treatment response is strongly shaped by disease heterogeneity across molecular, cellular, and structural levels. Antibody-defined subtypes, including acetylcholine receptor (AChR)-positive, muscle-specific tyrosine kinase (MuSK)-positive, low-density lipoprotein receptor-related protein 4 (LRP4)-positive, and seronegative MG, differ in immune mechanism, complement dependence, and therapeutic vulnerability. On this basis, neonatal Fc receptor (FcRn) antagonists, complement inhibitors, and B-cell-directed therapies have emerged as major biologic classes that increasingly enable mechanism-informed treatment selection. At the same time, resistance remains an important clinical problem, arising from persistent autoreactive immune compartments, pathway-level escape, and irreversible neuromuscular junction damage that may sustain disability despite immunological control. In this review, we discuss how immunological heterogeneity provides the biological rationale for targeted therapy in MG and synthesize current evidence for established and emerging biologics, including FcRn antagonists, complement inhibitors, B-cell- and plasma-cell-directed strategies, and cell-based immunotherapies. We further examine the major barriers that now define the field, particularly long-term safety, infection risk, treatment resistance, incomplete biomarker frameworks, and the distinction between active immune refractoriness and fixed structural impairment. Finally, we outline how biomarker-guided stratification, dynamic monitoring, and integration of neuroprotective or regenerative approaches may help move MG management from empiric escalation toward safer and more precise individualized care.

Ubiquitin-like modifier activating enzyme 1 (UBA1) occupies the apex of the canonical ubiquitination cascade and supplies activated ubiquitin to a broad network of E2 conjugating enzymes and E3 ligases. Although traditionally regarded as an essential housekeeping enzyme, human genetics has revealed a more instructive function for UBA1: it determines whether proteostatic stress is buffered, converted into inflammatory adaptation, or progresses to cell death. Somatic UBA1 mutations causing VEXAS syndrome provide a natural experiment in this threshold biology. Partial and compartment-selective loss of UBA1 activity permits hematopoietic cells to survive while reducing ubiquitination capacity, activating stress-response pathways, altering cell-death thresholds, and promoting innate immune dysregulation. Single-cell and functional studies further demonstrate early inflammatory activation in UBA1-mutant hematopoietic progenitors, myeloid-biased differentiation, monocyte dysfunction, and inflammasome-associated signaling. Conversely, profound pharmacological UBA1 inhibition with agents such as TAK-243 drives proteotoxic collapse and is being explored as an anticancer strategy. Here, we propose that UBA1 functions as a proteostasis-innate immunity checkpoint whose biological output is determined by residual enzymatic activity, subcellular distribution, lineage context, and clone size. This framework reconciles inflammatory disease caused by partial UBA1 dysfunction with the antitumor effects of UBA1 inhibition and suggests a mechanism-based approach to therapeutic intervention in VEXAS syndrome and malignancy.

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet durable responses remain inconsistent and clinically significant toxicities persist. Emerging evidence identifies the gut microbiota as an extratumoral determinant of CAR-T efficacy, persistence, and toxicity. However, taxonomic signatures associated with clinical outcomes show limited reproducibility and are influenced by antibiotics, geography, diet, and methodological heterogeneity. Building on prior reviews addressing microbiome-CAR-T associations and CAR-T-cell immunometabolism separately, here we synthesize clinical, translational, and preclinical evidence into an integrated, metabolome-centered framework spanning the full CAR-T treatment and manufacturing trajectory. Broad-spectrum antibiotic exposure disrupts microbial metabolic output, depleting short-chain fatty acids, indole derivatives, and other bioactive metabolites, and has been associated with inferior clinical outcomes in several cohorts, although these associations are heterogeneous and may be confounded by baseline disease severity, systemic inflammation, and infection-related factors. Experimental studies further indicate that butyrate, valerate, inosine, indoles, and succinate modulate mitochondrial fitness, memory differentiation, epigenetic programming, cytotoxicity, and exhaustion through interconnected metabolic and receptor-mediated pathways. We propose that the gut microbiota acts as a distributed metabolic organ whose collective output shapes CAR-T-cell fitness and therapeutic response. This framework supports the development of metabolite-based biomarkers and therapeutic strategies, including microbiota-conscious antibiotic stewardship, ecosystem restoration, dietary or metabolite-based interventions, and ex vivo metabolic conditioning during CAR-T manufacturing. Shifting from descriptive microbiome profiling to functional metabolomics may improve both prediction and optimization of CAR-T therapy.

The CODE (Comprehensive Oral Mucosa Database with Explanations) dataset is a publicly available smartphone-based intraoral image repository developed to facilitate artificial intelligence (AI) research in oral healthcare. The dataset was generated as part of the Indian Council of Medical Research (ICMR)-funded SMITA project using a standardized hub-and-spoke oral health screening framework implemented across Tamil Nadu, India. A total of 5,632 intraoral images were acquired from 704 participants using standardized smartphone imaging protocols, of which 5,566 images satisfied predefined quality assessment criteria and were included in the final dataset. The repository comprises 5,386 normative images and 180 abnormal images representing variations from normal oral mucosa, oral potentially malignant disorders (OPMDs), and oral cancer. Images were captured from predefined intraoral anatomical sites under standardized acquisition procedures and linked to anonymized participant-level demographic and clinical metadata. Expert-reviewed polygon annotations were generated using the VGG Image Annotator (VIA) platform and are provided in JSON format together with annotated and unannotated JPEG images and structured metadata files. Technical validation was performed using an unsupervised convolutional autoencoder to demonstrate the suitability of the dataset for representation learning and anomaly detection rather than diagnostic performance evaluation. The predominance of normative images reflects the intended purpose of the dataset as a resource for baseline anatomical feature learning, self-supervised learning, and anomaly detection. The CODE dataset provides a reusable benchmark resource for image segmentation, explainable AI, image quality assessment, tele-dentistry, multimodal learning, and future AI-assisted oral disease screening research.