Conventional carcinomas that lack neuroendocrine morphological features but display detectable expression of neuroendocrine markers through immunohistochemistry are termed conventional carcinomas with neuroendocrine differentiation (NED). Distinguishing these from mixed neuroendocrine non-neuroendocrine neoplasms and amphicrine-like carcinomas is important in accurate diagnosis and clinical management. The present review systematically outlines the advancements in research on gastrointestinal conventional carcinomas with NED, focusing on their characteristics, diagnostic criteria and clinical features. The present review further summarizes the epidemiological and clinical aspects across numerous organs such as the stomach and colorectum, emphasizing common mechanisms and prognostic variability. The future prospects of gastrointestinal conventional carcinomas with NED are also discussed, concentrating on key mechanisms, molecular subtypes and ongoing clinical trials to influence future research and clinical practices.

Cholesterol metabolism, hepatocellular carcinoma (HCC), and the tumor immune microenvironment are increasingly recognized as interconnected drivers of metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis-related HCC (MASLD/MASH-HCC). However, cholesterol dysregulation during hepatocarcinogenesis is often discussed as isolated pathways or single-stage events, and evidence strength differs across human HCC tissues, preclinical HCC models, and non-HCC systems. This review integrates mechanistic, spatial multi-omics, and translational evidence to highlight cholesterol dyshomeostasis as a stage- and cell-type-specific rewiring of synthesis, uptake, esterification, efflux, and conversion rather than a uniform metabolic increase. In chronic metabolic liver disease, sterol regulatory element-binding protein 2 (SREBP2)-SREBP cleavage-activating protein (SCAP) activation, impaired bile acid-farnesoid X receptor (FXR) feedback, free-cholesterol loading, and oxysterol accumulation may connect hepatocyte stress with stellate-cell activation, macrophage remodeling, inflammation, and fibrosis. During preneoplastic transition and early HCC, squalene epoxidase (SQLE), sterol O-acyltransferase 1 (SOAT1), farnesyl-diphosphate farnesyltransferase 1 (FDFT1), 24-dehydrocholesterol reductase (DHCR24), and SCAP-regulatory circuits may support membrane remodeling, oncogenic signaling, metabolic autonomy, and impaired immune surveillance, although their evidence levels vary. In advanced and metastatic HCC, spatially resolved studies suggest cholesterol-active tumor regions may be coupled to exhausted T cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), extracellular vesicle signaling, and oxysterol-mediated communication. We further discuss stage-aligned diagnostic and therapeutic opportunities, proposing cholesterol metabolic rewiring as a hypothesis-generating and partially validated framework for HCC initiation, progression, recurrence, and therapeutic resistance.

Immune checkpoint blockade has transformed cancer therapy by demonstrating that durable tumour control can be achieved through immune modulation rather than direct cytotoxicity. However, primary resistance remains the dominant clinical outcome across solid tumours, reflecting a fundamental limitation of checkpoint inhibitors: they do not initiate antitumour immunity, but amplify immune responses that are already underway. Here, we advance immune readiness as a unifying framework to explain primary resistance to immune checkpoint inhibitors. Immune readiness is defined as a dynamic and programmable host-tumour state characterised by competent innate sensing, type I interferon-driven myeloid activation, dendritic-cell licensing, coordinated antigen presentation, productive lymphocyte priming, and permissive inflammatory trafficking into tumour tissue. In the absence of these upstream processes, checkpoint blockade is biologically inconsequential, regardless of tumour antigenicity or checkpoint expression. Within this framework, therapeutic vaccination is positioned as a flexible immune-conditioning strategy that can induce, amplify, or synchronise immune readiness rather than as a direct cytotoxic modality or rigidly antecedent intervention. Tumour-directed, immune-modulatory, and tumour-agnostic vaccines may construct the immunological substrate required for checkpoint efficacy when integrated before, during, or in close temporal coordination with checkpoint blockade. Engineering immune readiness through vaccination-enabled immunotherapy offers a coherent strategy to overcome primary resistance and expand the therapeutic reach of cancer immunotherapy.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies, yet its efficacy in solid tumors and durability across broader application remain limited. A central challenge lies in how CAR signaling is initiated, amplified, and regulated over time. Unlike the native T cell receptor (TCR), CARs are synthetic, modular receptors whose signaling output is dictated by the composition and spatial organization of their extracellular, transmembrane, and intracellular domains. Emerging evidence suggests that CAR signaling requirements are not static: insufficient signaling at early time points can impair activation and tumor clearance, whereas excessive or prolonged signaling promotes exhaustion, toxicity, and loss of persistence. More recent CAR designs therefore emphasize fine-tuned signaling, embracing a "less-is-more" paradigm to balance potency with durability. In this review, we summarized recent advances in CAR signaling biology, focusing on temporal signaling thresholds, modular design principles, and emerging strategies to precisely control signal strength and quality. Finally, we discuss how high-throughput screening, computational modeling, and machine learning approaches may enable disease-specific, personalized CAR designs in the future.

Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) across multiple organ systems. Although inflammatory central nervous system irAEs (CNS inflammatory irAEs) are uncommon, they are often severe. Primary CNS tumors and brain metastases have distinct immune microenvironments, yet the heterogeneity of ICI-related inflammatory CNS irAE reporting signals across tumor phenotypes remains poorly understood.

We used pharmacovigilance signal discovery, external corroboration, and transcriptomic contextualization of pre-existing brain tumor immune landscapes. We constructed an ICI-exposed cohort from the FDA Adverse Event Reporting System (FAERS) and compared inflammatory CNS irAE disproportionality signals across primary CNS tumors, brain metastases, and non-CNS solid tumors. External comparison used the Japanese Adverse Drug Event Report database (JADER). Public single-cell RNA sequencing datasets were analyzed to characterize baseline strict inflammatory and broad stress-related modules across cellular compartments, with spatial transcriptomics used as secondary descriptive visualization in brain metastasis tissue.

In FAERS, inflammatory CNS irAE reporting signals suggested tumor phenotype-associated heterogeneity, with adjusted odds ratios of 1.65 (95% CI, 1.02-2.65) for primary CNS tumors and 3.12 (95% CI, 2.45-3.98) for brain metastases versus non-CNS solid tumors. Signals were stronger under a strict noninfectious phenotype and attenuated under a broad neuroinflammatory phenotype. Thyroid comparator analyses showed no comparable enrichment, whereas the myocarditis-related comparator was too sparse in the brain metastasis subgroup for meaningful inference. JADER showed a broadly similar pattern, although primary CNS tumor estimates were sparse and exploratory. Baseline single-cell analyses localized strict inflammatory module activity mainly to myeloid and T/NK compartments, while spatial maps served only as secondary descriptive visualization.

ICI-related inflammatory CNS irAE reporting signals suggested tumor phenotype-associated differences, most prominently in brain metastases. Stricter phenotype definitions appeared more specific than broader neuroinflammatory definitions. Public single-cell datasets characterized pre-existing immune-rich myeloid/T-NK compartments, while spatial maps provided only secondary descriptive tissue-level visualization and did not demonstrate irAE-onset tissue states. These pharmacovigilance findings should be interpreted as hypothesis-generating reporting associations, not evidence of incidence, absolute risk, or causality.

Chimeric Antigen Receptor-Natural Killer Cell (CAR-NK) is a promising next-generation immunotherapy. Persistence of CAR-NK cell therapy is considered a key hurdle limiting its full therapeutic potential. This review highlighted the causes of poor CAR-NK persistence and summarized strategies developed to improve CAR-NK persistence in both hematologic malignancies and solid tumors. These strategies included cytokine and cytokine signaling mediated strategies; optimization of NK cell source and CAR design; intrinsic and extrinsic checkpoint disruption and metabolic reprogramming; and lymphodepletion, alloevasion and fratricide evasion strategies. Multiple strategies that aim at improving in vivo persistence should prove useful in enhancing therapeutic efficacy of CAR-NK.

Malignant tumors remain a major global health burden, creating an urgent need for biomarkers and therapeutic targets that can improve diagnosis, prognostic stratification, and treatment. This review focuses on glioma-associated oncogene family zinc finger 3 (GLI3), a context-dependent transcription factor in the Hedgehog signaling pathway.

We integrated current evidence on GLI3 isoform processing, including the full-length activator GLI3A and the cleaved repressor GLI3R, as well as canonical and non-canonical regulatory mechanisms and the functional consequences of altered GLI3 signaling across diverse tumor types. The analysis revealed that GLI3 exerts both oncogenic and tumor-suppressive effects in a highly context-dependent manner. These effects are governed by the balance between GLI3A and GLI3R, tumor-specific signaling networks, and microenvironmental influences. Dysregulated GLI3 signaling is associated with epithelial-mesenchymal transition, cancer stem cell maintenance, immune remodeling, and therapeutic resistance. Moreover, GLI3 expression and isoform patterns show promise as diagnostic, prognostic, and susceptibility biomarkers. Emerging therapeutic strategies target GLI3 through indirect modulation, direct inhibition, or combination approaches. These findings highlight the potential clinical utility of GLI3.

This review identifies GLI3 as a pivotal regulator of tumor biology and highlights its potential as a promising target for precision oncology. Key challenges for future research include the development of isoform-specific detection methods, clarification of non-canonical regulatory mechanisms, and improved translational validation.

Thyroid cancer ranges from indolent differentiated tumors to metastatic, radioiodine-refractory and anaplastic disease. Conventional histology and molecular classification define major risk groups but do not resolve the cell states and spatial heterogeneity that accompany progression. This review integrates recent single-cell RNA sequencing, spatial transcriptomics and validation studies across localized papillary thyroid carcinoma (PTC), metastatic or radioiodine-refractory differentiated thyroid cancer (DTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC). Current evidence indicates that progression is accompanied by changes in malignant epithelial states, stromal regions and immune patterns. Malignant epithelial cells shift from follicular-like programs toward partial EMT-like, dedifferentiation-like and anaplastic states; stromal changes include invasive borders, stiff peritumoral matrix and CAF/ECM-rich poorly differentiated regions; and immune patterns differ between progressive PTC, indolent lymphoid-organized tumors and myeloid-rich ATC. Functionally supported examples, including POSTN-IL-4 signaling, CCL20/CXCL5 macrophage-tumor reciprocal signals and SIGLEC15-associated checkpoint signaling, show how these technologies can generate therapeutic hypotheses. Yet most datasets are cross-sectional, and many ligand-receptor interactions remain computational candidates. We use the available evidence to relate epithelial plasticity, genomic context, stromal regions, immune remodeling and candidate cell-cell interactions across disease states, while separating observed associations from established stepwise tumor evolution. This synthesis highlights mechanisms and therapeutic hypotheses that require functional and clinical validation.

Adult hemophagocytic lymphohistiocytosis (HLH) may be triggered by infection, malignancy, or systemic inflammatory disease. Attribution is challenging when recent SARS-CoV-2 infection, quiescent adult-onset Still's disease (AOSD), and an occult B-cell clonal disorder coexist.

A 71-year-old man with AOSD controlled for 14 years on low-dose methotrexate developed persistent fever and fatigue after mild SARS-CoV-2 infection. He subsequently developed cytopenias, hyperferritinemia, markedly elevated lactate dehydrogenase, diffuse FDG-avid lymphadenopathy, hepatosplenomegaly, elevated soluble interleukin-2 receptor, reduced natural killer-cell activity, and bone marrow hemophagocytosis, fulfilling HLH criteria. Broad pathogen evaluation, including blood and bone marrow metagenomic next-generation sequencing, did not identify an alternative infectious trigger. Bone marrow histopathology did not show definite tumor cells; however, flow cytometry identified monoclonal mature B cells, and peripheral-blood smear high-throughput sequencing detected lymphoma-associated mutations including MYD88, CD79B, IGLL5, PRDM1, DTX1, DUSP2, and BTG1. Multidisciplinary consultation favored probable lymphoma-associated HLH with clinically diagnosed stage IVB diffuse large B-cell lymphoma. HLH-directed therapy followed by rituximab-based lymphoma-directed chemotherapy led to transient clinical improvement, but the patient later died from infectious complications.

Mild SARS-CoV-2 infection may act as a co-trigger or unmasking event rather than the sole cause of HLH. Persistent high lactate dehydrogenase and soluble interleukin-2 receptor, diffuse lymphadenopathy, clonal mature B cells, lymphoma-associated mutations, and negative broad pathogen testing should prompt evaluation for occult lymphoma-associated HLH.

Bladder cancer, a common malignant tumor of the urinary system, possesses a highly heterogeneous tumor immune microenvironment that critically influences disease progression, treatment response, and patient prognosis. The limitations of traditional tissue biopsies have spurred interest in non-invasive, dynamic, and spatially resolved assessment strategies. Radiomics enables non-invasive quantification of macroscopic tumor phenotypes through high-throughput extraction of medical imaging features, while spatial omics technologies, such as single-cell and spatial transcriptomics, reveal the fine-grained spatial architecture of cellular and molecular components within the tumor microenvironment. This review systematically summarizes recent advances in radiomics and spatial omics for characterizing the bladder cancer immune microenvironment, with a focus on their synergistic applications in elucidating immune cell spatial distribution, stromal heterogeneity, immune checkpoint expression, and therapy response prediction. Furthermore, we critically examine the current challenges in multi-omics data integration, model generalization, and clinical translation, and outline future directions driven by artificial intelligence, including multimodal fusion, dynamic monitoring, and personalized therapeutic strategies. This review aims to provide a theoretical foundation and technical outlook for precision medicine in bladder cancer, facilitating the translation of imaging-spatial omics from basic research to clinical practice.