Small cell lung cancer is one of the most aggressive malignancies, characterized by rapid tumor growth, early metastatic spread and extremely poor survival. Although most patients initially respond to platinum-based chemotherapy, relapse is almost inevitable and treatment options at recurrence remain limited. The recent introduction of immune checkpoint inhibitors has provided only modest clinical benefit, largely due to the fact that these tumors are immunologically cold. These limitations highlight the urgent need to better understand the molecular features of small cell lung cancer in order to identify more effective therapeutic strategies. In this review, we summarize current knowledge of the molecular landscape of small cell lung cancer, with particular emphasis on transcriptome-based classifications that have identified four major molecular subtypes defined by distinct transcriptional regulators and gene expression programs. We discuss how these classifications have improved the biological understanding of the disease and stimulated efforts to develop subtype-specific therapeutic strategies. At the same time, we highlight important limitations of this framework, including the remarkable transcriptional plasticity of tumor cells, which allows dynamic transitions between subtypes and may contribute to therapeutic resistance. To address these challenges, we examine additional molecular features that may represent more stable vulnerabilities, including recurrent genomic alterations, such as the widespread loss of tumor suppressor genes or oncogene amplifications through extrachromosomal DNA. We also discuss emerging approaches aimed at identifying novel context-specific cancer dependencies, including genome-scale functional screens in vitro and in vivo and genetic restraint analyses. Finally, we consider the growing potential of liquid biopsy strategies, which exploit the high level of circulating tumor DNA in patients with this disease to detect clinically relevant genomic alterations and monitor tumor evolution. Overall, this review highlights both the opportunities and challenges associated with molecular stratification in small cell lung cancer. The integration of transcriptional classifications with genomic and functional approaches may help identify more robust therapeutic vulnerabilities and guide the development of more effective treatments for this highly aggressive disease.
Acute heart failure (AHF) remains a global health challenge, characterized by high morbidity, mortality, and frequent rehospitalizations. The heterogeneity of clinical presentations in AHF and its complex underlying pathophysiology complicates diagnosis, risk stratification, and therapeutic decision-making. Biomarkers have reshaped the clinical landscape in AHF by providing objective, biologically-grounded insights that complement traditional clinical assessment. Natriuretic peptides are established as indispensable for diagnosis and prognosis, while troponins, soluble ST2, galectin-3, and even newer candidates such as adrenomedullin and CA-125 may capture complementary domains including myocardial injury, fibrosis, congestion, and systemic stress. Applied dynamically across the care continuum—from the emergency department to hospitalization, discharge, and follow-up—biomarkers may support earlier diagnosis, more refined risk assessment, monitoring of therapeutic response, and post-discharge surveillance. Evidence increasingly favors multimarker strategies, integrating diverse biological signals; these consistently outperform single-marker approaches. Risk scores that incorporate biomarkers further strengthen clinical decision-making by providing structured risk estimates at critical time points. Future studies must explore best means of combining multiple markers into panels and whether multimarker-guided strategies have benefit in improving outcomes beyond the natriuretic peptides and troponin. Future advances will depend on embedding biomarkers within precision-medicine frameworks. Phenotype-specific algorithms, integration into electronic health records with automated decision support, and the application of artificial intelligence and machine learning offer clear potential. Equally, innovations in point-of-care testing and remote monitoring may extend biomarker utility beyond hospital walls. Collectively, these developments could shift AHF management from reactive stabilization toward proactive, biomarker-guided care aimed at improving outcomes in this high-risk population.
Kirsten rat sarcoma viral oncogene homolog (KRAS), a member of the small GTPase family, is the most frequently mutated RAS isoform in human cancers. It drives tumorigenesis and progression in various malignancies, including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC), and has long been considered an “undruggable” target. Recent advances in mutant-selective KRAS inhibition have reshaped this view, but therapeutic responses remain limited by adaptive resistance, tumor heterogeneity, and context-dependent signaling dependencies. This review focuses on how allele-specific biochemical properties, tissue context, and co-mutational backgrounds shape KRAS signaling output, tumor progression, therapeutic response, and resistance. We further discuss current diagnostic approaches and therapeutic strategies, ranging from direct mutant-selective inhibitors to pathway-targeted combinations, degraders, immunotherapies, RNA-based approaches, and exosome-mediated delivery. Finally, we highlight key challenges including adaptive resistance, tumor heterogeneity, allele-specific druggability, and the need for biomarker-guided combination strategies. Together, this review provides a framework for understanding KRAS-mutant cancers as biologically diverse diseases and for guiding the development of more precise and durable therapeutic strategies.
Bone metastasis (BM) frequently occurs in various types of cancer, particularly in prostate (PCa), breast (BCa), renal (RCC), and lung cancers (LCa), yet no reliable biomarker has been established. In this study, we evaluated the clinical utility of serum growth differentiation factor 15 propeptide (sGDPP), secreted by both osteoblasts and osteoclasts, as a diagnostic biomarker for BM across common solid tumors. A total of 799 participants were enrolled, including 107 healthy donors, 242 patients with PCa, 113 patients with BCa, 159 patients with RCC, and 178 patients with LCa. Among the cancer patients, 398 had no BM and 294 had BM. The diagnostic performance for BM was compared among conventional biomarkers: alkaline phosphatase (ALP), lactate dehydrogenase (LDH), estimated glomerular filtration rate, osteocalcin, bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase 5b, procollagen type I N-terminal propeptide (PⅠNP), and sGDPP. Among all patients, ALP, LDH, PⅠNP, and sGDPP levels were significantly higher in patients with BM than in those without BM. Particularly, sGDPP showed the highest area under the curve values (0.91 in PCa, 0.80 in BCa, 0.81 in RCC, and 0.51 in LCa). Multivariate analysis showed sGDPP is an independent diagnostic biomarker for BM in PCa, BCa, and RCC (p < 0.01). Additionally, sGDPP in patients with osteoporosis did not significantly differ from that in healthy donors, suggesting that sGDPP increases only when tumor cells seed and proliferate in the bones. Overall, sGDPP demonstrated superior diagnostic performance compared to conventional biomarkers and may complement imaging tests in detecting BM.
Recent phase I/II clinical trials have demonstrated that chimeric antigen receptor (CAR) T cells targeting the disialogangliosade GD2 represent a promising therapeutic option for pediatric patients with relapsed or refractory high-risk neuroblastoma (NB). However, incomplete and heterogeneous clinical responses highlight the need to improve CAR T-cell efficacy and persistence. We previously demonstrated the therapeutic benefit of combining the dual insulin-like growth factor 1 receptor/insulin receptor (IGF1R/IR) inhibitor linsitinib (LIN) with third-generation GD2.CAR T cells in diffuse intrinsic pontine glioma, where LIN induced tumor cell death and modulated the CAR T-cell phenotype. Here, we extended these findings to NB and explored the mechanisms of LIN-mediated CAR T-cell modulation. LIN, in combination with CAR T cells, significantly enhanced antitumor activity in LIN-sensitive NB cell lines. Mechanistically, we investigated ferrochelatase (FECH), a mitochondrial enzyme involved in heme biosynthesis, and a known off-target of LIN. LIN treatment or selective FECH inhibition with N-methyl protoporphyrin IX reduced intracellular heme, attenuated activation and exhaustion marker expression and promoted central memory characteristics associated with improved in vivo CAR T-cell persistence and functionality. Both treatments similarly decreased ATP production by reducing glycolysis and mitochondrial respiration in chronical antigen-activated CAR T cells. Collectively, these data reveal a dual mechanism of action for LIN, combining direct tumor cell cytotoxicity with metabolic reprogramming of CAR T cells linked to heme biosynthesis. These findings identify heme metabolism as regulator of CAR T-cell phenotype and function and support further investigation of FECH to enhance therapeutic efficacy in NB and beyond.
Although chimeric antigen receptor T-cell (CAR-T) therapy has reshaped the treatment landscape for relapsed/refractory multiple myeloma (RRMM), durable remission remains challenging. T-cell dysfunction and exhaustion are key obstacles to long-term efficacy. Programmed death-ligand 1 (PD-L1)-positive exosomes may contribute to tumor-associated immunosuppression, but their clinical and functional relevance in multiple myeloma (MM) remains unclear. A total of 89 patients with MM were enrolled, including 34 patients with RRMM treated with CAR-T therapy. PD-L1+ exosome levels in peripheral blood (PB) and bone marrow (BM) were quantified by flow cytometry using exosome-coupled beads, and soluble PD-L1 (sPD-L1) was measured by enzyme-linked immunosorbent assay. Associations with clinicopathological features, treatment response, and progression-free survival (PFS) were analyzed. Effects of RRMM patient sample-derived PD-L1+ exosomes on CD8+ T-cell activation, cytokine production, and exhaustion phenotypes were assessed using in vitro experiments. The therapeutic potential of GW4869 combined with anti-programmed cell death protein 1 (PD-1) antibody to enhance CAR-T efficacy was further evaluated using in vitro and in vivo models. PD-L1+ exosome levels in PB and BM were significantly elevated in newly diagnosed MM and RRMM compared with healthy controls, and were closely associated with adverse prognostic features, including high tumor burden, extramedullary lesions, and high-risk cytogenetic features, whereas plasma sPD-L1 showed no significant clinical correlations. In RRMM patients receiving CAR-T therapy, pretreatment BM and PB PD-L1+ exosome levels discriminated best response (complete response versus less than complete response), with BM showing better predictive performance (area under the receiver operating characteristic curve, 0.846; optimal cutoff, 65.0
Cancer of Unknown Primary (CUP) presents substantial diagnostic and therapeutic challenges owing to its heterogeneous nature and the absence of an identifiable primary tumor site. This review provides a structured search of the pathogenesis, epidemiological characteristics, and limitations of traditional diagnostic and therapeutic approaches for CUP, with an emphasis on the evolution of Tissue of Origin (TOO) identification techniques. Recent advances in precision medicine have accelerated the development of machine learning–based TOO identification tools, representing a paradigm shift in CUP diagnostics. Deep learning (DL) algorithms that integrate multi-omics data (such as genomics and transcriptomics) with clinical features have markedly enhanced the accuracy of tracing tumor origin, and artificial intelligence (AI) driven TOO models are increasingly being incorporated into clinical practice, offering new insights for pathological diagnosis, treatment selection, and prognostic evaluation. Nevertheless, several challenges remain, including issues of data standardization, model generalizability, and interpretability. Ethical considerations related to data privacy, algorithmic fairness, and clinical implementation also warrant careful attention. Future research should focus on establishing standardized multi-center databases, developing more interpretable AI models, and fostering multidisciplinary collaborative strategies for CUP management. Through continued refinement of technical solutions and regulatory guidelines, TOO identification is anticipated to progress from research to routine clinical application, ultimately supporting precise and personalized care for patients with CUP.
Breast cancer stemness drives tumor progression and therapy resistance, yet the underlying mechanisms remain poorly understood. In this study, we observed that RBM38 expression gradually decreases during breast cancer progression in MMTV-PyMT transgenic mice. Using a model with targeted RBM38 expression in breast tissue, we found it suppressed tumor initiation, decreased tumor size and metastasis, and reduced breast cancer stem cells. Multi-omics analyses, including single-cell and spatial transcriptomics, RIP-sequencing, and proteomics, were used to reveal the mechanisms. We identified HOXD10 mRNA as a critical downstream target of RBM38. Phosphorylation of RBM38 at Ser117, Thr120, and Thr132 by SLK and PGAM5 is required for RBM38-mediated stemness suppression, protein complex formation, and HOXD10 mRNA regulation. Based on these insights, we explored RBM38’s therapeutic potential using an activatable supercharged polypeptide (ASCP) delivery platform. In patient-derived xenograft (PDX) models, ASCP-RBM38 achieved effective tumor localization, reduced stemness, and protected against doxorubicin (DOX)-induced cardiotoxicity. Clinical analysis of human samples validated this mechanism. Our study underscores the pivotal role of phosphorylation-mediated regulation and protein complex formation in RBM38-mediated control of breast cancer stemness, highlighting its therapeutic potential.
Pancreatic cancer remains one of the most lethal malignancies worldwide, with pancreatic ductal adenocarcinoma (PDAC) accounting for the majority of cases and exhibiting a persistently poor prognosis. Although chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable success in hematological malignancies, its therapeutic efficacy in pancreatic cancer remains limited. This review summarizes recent advances in CAR-T cell therapy for pancreatic cancer, with a focus on representative tumor-associated targets, including mesothelin (MSLN), claudin 18.2 (CLDN18.2), prostate stem cell antigen (PSCA), CD155, CD276, growth arrest-specific protein 6 (GAS6), and glypican-1 (GPC1), while also highlighting emerging next-generation CAR-T engineering strategies, including nanobody-based antigen recognition, cytokine-armored CAR-T cells, allogeneic CAR-NKT platforms, dual-target and logic-gated CAR systems, and innovative delivery approaches. Current preclinical and early clinical evidence suggests that several targets, particularly MSLN and CLDN18.2, show promising antitumor activity; however, durable clinical responses remain difficult to achieve. The major barriers include the dense desmoplastic stroma, highly immunosuppressive tumor microenvironment (TME), antigen heterogeneity, antigen loss, limited CAR-T persistence and expansion, T-cell exhaustion, and on-target, off-tumor toxicity. To overcome these obstacles, emerging strategies have focused on remodeling the TME, engineering armored or dual-target CAR-T cells, developing logic-gated CAR systems, improving CAR-T persistence, and optimizing delivery approaches through nanomaterials, oncolytic viruses, in situ CAR-T generation, alternative immune-cell carriers, and locoregional administration. Overall, CAR-T therapy for pancreatic cancer is progressing from preclinical exploration toward clinical translation. Future success will likely depend on rational target selection, multi-dimensional TME modulation, advanced CAR engineering, precision delivery, and biomarker-guided patient stratification.
The 2025 American Society of Hematology (ASH) Annual Meeting highlighted rapid advances in gene editing for hematologic diseases, with increasing emphasis on precision editing and early exploration of in vivo delivery strategies. Beyond technological development, several measurable parameters are emerging as potential biomarkers, including fetal hemoglobin (HbF), F-cell proportion, HbF/F-cell, editing durability, and long-term clonal monitoring. Clinical studies demonstrated that disruption of the BCL11A enhancer or editing of the HBG1/2 promoter can induce sustained HbF reactivation, which is associated with reduced transfusion burden or transfusion independence in transfusion-dependent β-thalassemia and improved clinical outcomes in sickle cell disease. Near-pancellular HbF distribution and HbF/F-cell levels above anti-sickling thresholds further support the pharmacodynamic value of HbF-related biomarkers. Long-term follow-up studies have also incorporated editing durability and clonal monitoring into safety assessment frameworks. Emerging platforms such as RNA Gene Writer and CD90-targeted virus-like particles have demonstrated the feasibility of in vivo hematopoietic stem cell editing, although challenges related to targeting efficiency, delivery specificity, immunogenicity, and long-term safety remain. Overall, ASH 2025 suggests a shift from achieving gene editing to quantifying efficacy, durability, and safety, with standardized biomarker frameworks likely to play an increasingly important role in future clinical translation.
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for relapsed or refractory hematologic malignancies, producing high remission rates in otherwise treatment-resistant patients. However, primary resistance and disease relapse remain common, particularly in solid tumors, limiting long-term benefit and broader clinical applicability. As the population of patients failing therapy grows, there is an urgent need for an integrated understanding of resistance mechanisms and a structured approach to salvage therapy. This review proposes a conceptual “Why-How-What if” framework to navigate the complexities of treatment failure. We first address “Why” therapy fails, identifying multifactorial drivers including tumor-intrinsic factors like antigen loss and immune evasion, T cell-intrinsic dysfunction such as exhaustion and limited persistence, and extrinsic constraints imposed by an immunosuppressive tumor microenvironment. We then explore “How” to enhance efficacy through mechanism-based strategies. These include rational combination approaches with immune checkpoint inhibitors or small molecule inhibitors, and next-generation engineering such as dual-target, armored, and in vivo generated CAR-T cells aimed at overcoming metabolic and physical barriers. Finally, we address the “What if” of treatment failure by summarizing individualized salvage options, for which current clinical evidence is derived predominantly from hematologic malignancies. These strategies range from target-switching and bispecific antibodies to emerging cellular platforms like CAR-natural killer cells and consolidation via allogeneic hematopoietic stem cell transplantation. By integrating mechanisms of failure with evolving optimization and salvage strategies, this framework provides a practical roadmap for clinical and translational progress. Future success will depend on biomarker-guided combinations and the continued diversification of adoptive cell therapy platforms.
Laccase domain containing 1 (LACC1) is an enzyme abundantly expressed in inflammatory macrophages that regulate diverse inflammatory diseases. This study aimed to investigate the role of LACC1 in lipopolysaccharide (LPS)-induced acute lung injury (ALI) and to elucidate its underlying regulatory mechanisms. Single-cell RNA sequencing of bronchoalveolar lavage fluid (BALF) from patients with ALI was performed to characterize LACC1 expression patterns in pulmonary macrophages. Then, LACC1 conditional knockout mouse model was established to investigate the in vivo function of LACC1 during LPS-induced lung injury. ln vitro function of LACC1 was further explored using LACC1-silenced THP-1 cells. RNA sequencing was conducted to profile gene expression changes in LACC1-knockdown THP-1 cells, followed by GO and KEGG enrichment analysis. Key downstream molecules and signaling pathways modulated by LACC1 were validated by Western blot and qRT-PCR. Single-cell RNA sequencing analysis based on BALF of ALI patients revealed that LACC1 expression was markedly elevated in pulmonary macrophages. Conditional knockout of LACC1 in macrophages exacerbated LPS-induced pulmonary inflammation. In vitro, LACC1 knockdown in THP-1 cells markedly exacerbated the inflammatory response after LPS treatment. RNA sequencing identified LPAR3 as a key downstream target, and enrichment analysis indicated significant involvement of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway followed by LACC1 knockdown. Western blot analysis confirmed that LACC1 knockdown reduced LPAR3 expression and inhibited PI3K/AKT/mTOR pathway activation. LACC1 might exert a protective effect against LPS-induced lung injury by suppressing inflammatory responses via modulation of LPAR3/PI3K/AKT/mTOR signaling pathway.
Mantle Cell Lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma, with frequent relapses and shorter responses with every subsequent treatment. MCL depends on growth factors and cytokines derived from microenvironmental cells for its growth and can alter the immune system to evade recognition and subsequent elimination. The soluble factors secreted by MCL can contribute to endothelial differentiation, lymphangiogenesis, and clonal selection under hypoxic conditions, thereby evading the DNA damage response. Targeting the tumor microenvironment and angiogenesis is an active area of research and development, as the angiogenic gene signatures in MCL remain poorly understood. To address this knowledge gap, we performed transcriptomic analyses of MCL patient cohorts and identified 10 key angiogenic genes upregulated in MCL. We focused on four receptors (FGFR1, VEGFR1, VEGFR2, and PDGFRB) that have receptor tyrosine kinase activity and are localized to the plasma membranes of MCL cells. These receptors were assessed for therapeutic targeting potential in four independent preclinical models, including patient-derived xenografts, cell-derived xenografts, bone marrow-derived xenografts, and a genetically engineered murine model of MCL. Our work establishes that simultaneous targeting of multiple kinases, such as FGFR1 and VEGFR2, is a promising therapeutic strategy for patients with MCL.
The circadian clock orchestrates many key physiological processes related to anti-tumor immunity, including the cell cycle, energy metabolism, immune infiltration, and cytokine secretion. Increasing evidence suggests that circadian clock disruption is involved in tumorigenesis and tumor progression. Both clinical and basic research indicate that the circadian clock is a central regulator of tumor immunity and an important target for intervention. However, the role of the circadian clock in remodeling tumor immunity, as well as existing and potential intervention strategies, remains largely uncharacterized. To investigate the role of the circadian clock in tumor immunity, we integrated a tumor-related circadian regulatory framework encompassing the central pacemaker, peripheral cell-autonomous clocks, and environmental and behavioral factors such as sleep and feeding. Evidence from epidemiological, clinical, and translational studies reveals that circadian disruption impairs immune surveillance and promotes tumor initiation and progression, contributing to increased cancer risk and poorer outcomes. We further examine the mechanisms by which circadian dysregulation reshapes the tumor immune microenvironment and alters both innate and adaptive antitumor immunity. Finally, we discuss emerging therapeutic approaches that leverage circadian biology to enhance antitumor immune responses, including circadian clock-targeting interventions and chronotherapy, highlighting their potential to improve cancer treatment outcomes. Evidence reviewed here indicates that circadian dysregulation promotes tumor progression through cell-intrinsic clock reprogramming and remodeling of the tumor immune microenvironment. By regulating immune surveillance, metabolic homeostasis, and the function of both immune effector and immunoregulatory cells, the circadian clock plays a central role in antitumor immunity. These findings support the integration of chronotherapy and circadian clock-targeting strategies with immunotherapy to improve the precision and efficacy of cancer treatment.
Lysosomes serve as central degradative hubs in cells, playing critical roles in maintaining protein homeostasis, clearing damaged organelles, and regulating metabolic signaling. Tumor cells heavily rely on lysosomal functions during proliferation, invasion, and drug resistance, a dependency that concurrently endows them with inherent susceptibility to lysosomal membrane permeabilization (LMP). Current cancer therapies rely heavily on surgical resection for early-stage disease, and chemotherapy or radiotherapy for advanced-stage cancers, but these modalities are limited by poor efficacy, severe side effects, and drug resistance. Therefore, targeting LMP to induce lysosome-dependent cell death (LDCD) represents a promising breakthrough. This review systematically summarizes the molecular mechanisms underlying LMP initiation and execution, as well as the regulatory pathways of LDCD modalities, including apoptosis, necroptosis, ferroptosis, pyroptosis, immunogenic cell death, and autophagy-dependent death. It further highlights the dual roles of lysosomes and LDCD in the tumor microenvironment and their core functions in tumor progression. Additionally, we outline classic therapeutic strategies targeting LMP and novel lysosome-targeting technologies, and discuss combination therapy regimens based on lysosomal modulation. These advances provide comprehensive theoretical foundations and new insights for the development of broad-spectrum lysosome centered anticancer drugs.
Postoperative recurrence remains a major obstacle to durable remission in patients with solid tumors, even after complete macroscopic resection. Growing evidence suggests that surgery creates a transient yet highly permissive biological window characterized by inflammatory signaling, coagulation activation, endothelial disruption, and systemic immune suppression. Together, these processes foster a protective niche that enables microscopic residual disease to evade immune surveillance and initiate metastatic outgrowth. Although modern adjuvant therapies have improved outcomes, their effectiveness is often limited by inadequate tumor-site specificity, systemic toxicity, poor immune cell trafficking, and tumor heterogeneity. Consequently, a critical unmet clinical need persists for biologically precise strategies capable of eliminating residual tumor cells at their point of vulnerability. Platelets, traditionally viewed as mediators of hemostasis, are now recognized as active regulators of tumor progression. By facilitating fibrin deposition, shielding circulating tumor cells from immune attack, and shaping inflammatory networks, platelets inadvertently support the survival of postoperative tumors. Paradoxically, these same wound-targeting properties create a compelling therapeutic opportunity: leveraging platelet-driven homing mechanisms to direct immunotherapy precisely to fibrin-rich surgical beds where recurrence often originates. In this review, we propose a platelet-guided CAR-T platform that leverages endogenous wound biology to create a precision immunotherapeutic delivery system. This strategy integrates platelet membrane cloaking or platelet–CAR-T conjugation with thrombin-responsive biomaterial depots to enhance local effector retention, amplify effector-to-target ratios, and prolong functional persistence. Programmable safety features, including affinity tuning, logic-gated activation, and inducible suicide switches, are used to reduce thrombo-inflammatory risk while preserving therapeutic efficacy. These mechanisms restrict activity to appropriate contexts and allow controlled shutdown in case of adverse events, improving overall safety. When coupled with minimal residual disease–guided patient selection using circulating biomarkers, this approach establishes a clinically actionable framework for perioperative intervention. Emerging preclinical evidence suggests that localized platelet-assisted delivery can reduce circulating tumor cell burden, enhance antigen presentation when combined with immune adjuvants, and suppress recurrence more effectively than systemic therapies. With rigorous safety validation, scalable manufacturing, and biomarker-enriched clinical trials, platelet-guided CAR-T therapy has the potential to transform the postoperative microenvironment from a sanctuary of tumor survival into a targeted domain for durable immune-mediated eradication. Clinical trial number Not applicable. Identifies the postoperative fibrin-rich niche as a transient, targetable reservoir for microscopic residual disease. Introduces platelet-guided CAR-T delivery via membrane cloaking or platelet–T cell conjugation with thrombin-responsive biomaterial depots. Enables spatially confined immune activation within the perioperative fibrin scaffold. Integrates programmable safety circuits (affinity tuning, logic gating, suicide switches) to limit systemic toxicity and thromboinflammation. Proposes MRD-guided perioperative stratification using ctDNA and circulating biomarkers. Demonstrates preclinical enhancement of local effector function, reduced tumor dissemination, and superior recurrence control. Defines a translational roadmap spanning GLP safety profiling, GMP platelet engineering, and biomarker-enriched adaptive trials.
Adult T cell leukemia (ATL) is defined as a mature T cell neoplasm caused by human T cell leukemia virus type 1 (HTLV-1) and has been ascribed to the HTLV-1 gene products. However, the presence of asymptomatic carriers (ACs) accounting for the majority of HTLV-1 infected individuals who pass entire lives without developing ATL suggests that HTLV-1 infection alone is not sufficient for the onset of ATL. Studies with chronologically collected specimens from ATL patients or pre-onset individuals reported the presence of HTLV-1 infected CD4+ CD7+ CD45RA+ T cells in blood in HTLV-1 ACs and the step wise development of malignant clones from CD7+ T cells, indicating that ATL is caused by accumulation of driver gene mutations as other cancers in general. Epidemiologically, mother-to-child infection of HTLV-1 during neonatal period is known to be the most important determinant of overall ATL incidence. This observation has attracted attention as getting to the core of the matter but has lacked hitherto any appropriate reasoning. Recent progress in basic immunology has disclosed that neonatal naïve T cells are, distinct from adult naïve T cells, exceptionally long-living and have propensity toward regulatory T cells. A minor population of stem cell like memory T cell (Tscm)-like HTLV-1 infected cells were detected in ATL patients and reported to repopulate ATL clones in immunodeficient mice. In this context, we need to trace the origin of ATL to HTLV-1 infected CD7+ T cells or Tscm in blood in ACs, and further to HTLV-1 infected neonatal naïve T cells. Latent infection of HTLV-1 has long-term effects on naïve T cells not only by viral gene products but also through their own pattern-recognition receptor-mediated reactions. In sum, the distinctive feature of ATL lies in its origin which may involve a neonatal naïve T cell and persistence of HTLV-1 provirus. The latter facilitates driver gene mutations when the infected cell increases frequency of cell division in the middle age of life.
IDH mutant gliomas, driven by the oncometabolite 2-hydroxyglutarate (2-HG), are associated with profound neurological morbidity and premature mortality. To address the unmet therapeutic needs, we investigated the mechanistic interplay between MTHFD2-driven one-carbon metabolism and ferroptosis susceptibility in these tumors. Our findings revealed that MTHFD2 upregulation, mediated through loss of m5C modification in chromatin associated RNAs (caRNAs)—establishes a metabolic vulnerability to ferroptosis. Crucially, we identified TAF15 as a pivotal RNA-binding protein that orchestrates the spatial recruitment of TET2 by bridging NSUN5-mediated RNA m5C methylation. Therapeutically, combinatorial targeting of MTHFD2 with its selective inhibitor and the hypomethylating agent decitabine induced ferroptosis in patient-derived IDH-mut glioma organoids, demonstrating potent ferroptosis activation. This work delineates an RNA epitranscriptomic-metabolism axis in glioma pathogenesis and provides a translational roadmap for exploiting metabolic dependencies in IDH-driven malignancies. Not applicable.
Ampulla of Vater (AoV) carcinoma is a rare malignancy arising at the junction of intestinal and pancreatobiliary epithelium. Its heterogeneous clinical behavior and histological diversity have hindered therapeutic advances, and the cellular basis of this heterogeneity remains unclear. We aimed to construct a single-cell transcriptomic atlas of AoV carcinoma, with a focus on identifying epithelial subtypes and their interactions with the tumor microenvironment (TME). We performed single-cell RNA sequencing on eight primary AoV tumors and four matched normal tissues. Comprehensive clustering and transcriptomic analyses identified cell-type composition, epithelial heterogeneity, and tumor-immune interactions. Findings were validated using deconvolution of bulk RNA-seq data from 62 AoV carcinoma patients. Results Malignant epithelial cells were categorized into four distinct subtypes: Int-Wnt, PB-KRAS, Int-Hypoxia, and Cycling stage. PB-KRAS cells exhibited stem-like transcriptional programs and high genomic instability. Deconvolution analysis of bulk RNA-seq data from the independent AoV cohort revealed that enrichment of the PB-KRAS subtype correlated with tumor recurrence and poor survival. Our immune profiling analysis discovered a significant association between PB-KRAS subtype and GZMK+ CD8+ T cells, which are in a pre-dysfunctional state, alongside SPP1+ macrophages exhibiting immunosuppressive traits. Spatial transcriptome data further supports the immunosuppressive natures of TME around PB-KRAS subtype malignant epithelial cells in AoV carcinoma. Our study presents a single-cell atlas of AoV carcinoma, highlighting the molecular diversity of malignant epithelium and its association with the immune microenvironment. The PB-KRAS subtype emerges as a stem-like, immunosuppressive tumor state associated with poor prognosis, providing insights for future therapeutic targeting.
Glucocorticoids(GCs) are widely used to treat erythropoietin-resistant anemias, yet the precise mechanisms underlying their erythropoiesis-promoting effects remain incompletely understood. This study used single-cell RNA sequencing, ATAC-seq, ChIP-seq, RNA-seq,quantitative PCR (qPCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry in vivo models (AIHA patients, CD163-/- mice, Gypa-eGFP-cremice, Epor-tdtomato-cre mice, and Epor-eGFP-cre rats) and in vitro human erythroblastic island(EBI) formation and EBI enrichment and cytospins, Giemsa and Prussian blue staining, quantification and co-culture systems to delineate CD163+ macrophages coordinating erythroblastic island formation and iron metabolism. GC promote erythropoiesis by regulating CD163-mediated EBI formation and modulating iron metabolism within EBI macrophages, a phenomenon conserved across humans, rats, and mice. We demonstrated that CD163+macrophages-but not their CD163- counterparts-exhibit heightened iron metabolism in the bone marrow, and that GC-induced erythropoiesis is markedly attenuated in CD163-deficient mice due to disrupted EBI architecture and impaired iron handling. Importantly, GC therapy restores iron metabolism and mitigates inflammatory responses in BM CD163+macrophages, likely contributing to improved erythropoiesis in patients with autoimmune hemolytic anemia. CD163⁺macrophages support GC-induced erythropoiesis by coordinating erythroblastic island formation and iron metabolism. These findings uncover a previously unrecognized GC-CD163-EBI axis that governs erythropoiesis and highlight the potential of targeting EBI macrophage function as a novel therapeutic strategy for anemia.
