Experimental Hematology & Oncology最新文献

Acute myeloid leukemia (AML) remains one of the most aggressive and treatment-resistant hematologic malignancies, driven by clonal expansion of immature myeloid blasts in the bone marrow and peripheral blood. Current therapies-chemotherapy and targeted agents-are limited by poor marrow penetration, systemic toxicity, and rapid development of resistant clones, leaving long-term survival rates low. Clinicians face the persistent challenge of delivering effective therapy while minimizing harm. Platelets and neutrophils-beyond their classical roles in hemostasis and innate immunity-actively support leukemic niches, suppress anti-tumor immunity, and protect malignant cells from cytotoxic attack. These interactions highlight an untapped opportunity: harnessing endogenous cellular networks to deliver therapeutics with precision and potency. Conventional carriers, including liposomes and nanoparticles, fail to exploit these natural trafficking and immune-modulatory mechanisms, limiting marrow-specific targeting and therapeutic durability. We propose cellular hitchhiking using patient-derived platelets and neutrophils as a transformative, patient-tailored strategy. These carriers leverage intrinsic homing mechanisms, immune interface modulation, and prolonged circulation to deliver cytotoxic, immunomodulatory, or gene-based therapeutics directly to marrow and sanctuary sites. Ex vivo priming, biomaterial functionalization, and patient-specific engineering can enhance marrow-targeted drug concentration by several-fold, reduce systemic exposure, and minimize thrombo-inflammatory complications. By converting circulating blood cells into programmable delivery vectors, this approach offers a biologically rational platform with translational potential; however, immediate clinical relevance requires validation in controlled early-phase human studies. Preclinical evidence indicates that cellular hitchhiking can substantially increase bone-marrow drug delivery and reduce systemic exposure; whether these improvements will translate into higher remission rates or lower relapse in patients remains to be established in prospective clinical studies. Integrated into AML management, this strategy provides a biologically rational platform with translational potential; careful preclinical de-risking and early-phase clinical trials are required to determine clinical relevance.

Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. The tumor immune microenvironment (TIME) significantly influences ferroptosis sensitivity in both cancer and immune cells. Recent years have witnessed major advances in understanding how multi-level regulatory mechanisms control ferroptosis in tumors, encompassing epigenetic modifications and post-translational protein regulation. Epigenetic mechanisms include DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, while post-translational modifications (PTMs) involve phosphorylation, glycosylation, ubiquitination, acetylation, methylation, and lactylation of key ferroptosis proteins. This review examines the intricate relationship between the TIME, ferroptosis, and these dual regulatory networks. We focus particularly on how epigenetic processes and PTMs synergistically control ferroptosis mediators in the TIME, exploring how ubiquitination controls protein stability, and how metabolic modifications like lactylation link cellular metabolism to ferroptosis regulation. These multilevel interactions create a complex regulatory landscape that influences cancer progression, immune evasion, and therapeutic resistance. The crosstalk between epigenetic and post-translational regulation determines ferroptosis susceptibility across different cellular contexts within tumors, with distinct modification patterns observed in cancer cells versus immune infiltrates. Additionally, we discuss emerging therapeutic strategies that simultaneously target both epigenetic and post-translational regulation of ferroptosis, including combination approaches that modulate specific modification enzymes to enhance ferroptosis induction. Understanding these complex multilevel regulatory relationships provides valuable insights for developing novel precision cancer treatment approaches that leverage the therapeutic potential of ferroptosis modulation with potentially significant clinical impact.

Background: Tumor histology reflects disease aggressiveness and clinical outcomes in cancer patients. Lung adenocarcinomas (LUADs) are classified based on predominant histologic patterns, including high-grade micropapillary and solid subtypes which portend unfavorable clinical features and prognosis. However, the cellular and molecular characteristics underlying these histologic subtypes remain largely unknown.

Methods: We used scRNA-seq to profile 117,266 cells from 18 treatment-naïve LUADs with heterogeneous histologic patterns and also performed spatial transcriptomic analysis (10x Visium) for representative cases. By integrating single-cell transcriptomics with spatial information, we aimed to characterize the cellular identity and spatial organization driving LUAD heterogeneity.

Results: We demonstrated that histologic subtypes can be distinguished by subtype-specific cancer cell subpopulations and immunosuppressive phenotypes in the tumor microenvironment (TME). Our data reveal how intercellular interactions among cancer cells, macrophages, and CD8⁺ T cells in the prognostically unfavorable solid subtype are associated with cancer cell plasticity and promote an immunosuppressive TME. Additionally, we identify HMGA1 as a potential clinically relevant biomarker and therapeutic target for the solid subtype LUAD.

Conclusions: These findings deepen our understanding of the histologic heterogeneity of LUAD and may facilitate the development of subtype-specific biomarkers and targeted therapeutic strategies.

Tolerogenic dendritic cells (tolDCs) hold promise for treating autoimmune diseases, potentially restoring antigen-specific immune tolerance without systemic immunosuppression. However, their behavior in vivo remains incompletely understood, particularly in response to microenvironmental factors such as oxygen (O₂) tension. While tolDCs are typically generated and functionally validated under atmospheric O₂ (21%), physiological O₂ levels (physioxia) in human tissues are considerably lower (3-9%). The primary aim of this study was to assess whether tolDCs manufactured under atmospheric O₂ conditions retain their function under physioxia at 4% O₂, mimicking tissue environments encountered upon clinical administration. To contextualize these findings, we also evaluated the effect of physioxia during in vitro generation and investigated underlying metabolic adaptations. We demonstrate that tolDCs generated under atmospheric O₂ conditions remain functionally effective in physioxic environments, preserving migratory capacity and the ability to induce T cell hyporesponsiveness. Furthermore, physioxia during tolDC generation impaired monocyte-to-tolDC differentiation efficiency, whereas hallmark tolerogenic features, including low expression of CD80, CD83, and CD86, remained intact. Metabolic profiling revealed a distinct shift under physioxia, with reduced mitochondrial reserve capacity and increased glycolytic activity. This suggests metabolic plasticity without loss of function across O₂ environments. Our findings indicate that physiological O₂ shapes tolDC differentiation and metabolism but does not compromise immunoregulatory traits. Importantly, tolDCs generated under atmospheric O₂ remained functionally competent in physioxic environments, reinforcing their suitability for therapeutic use. By modeling in vivo-relevant O₂ levels, this study provides new insights into how microenvironmental O₂ may shape tolDC behavior following clinical administration.

Background: The genes controlling lineage determination and differentiation tend to be essential for the development of acute myeloid leukemia (AML). Identifying novel target genes capable of promoting the differentiation and maturation of undifferentiated leukemia cells offers a promising therapeutic strategy for the treatment of AML.

Methods: We used conditional Elk1 and KrasG12D expression mice, along with Mx1-Cre, Lyz2-Cre and Elane-Cre drive strains (which enable stage specific control of Elk1 or KrasG12D expression), to investigate the function of Elk1 in the hematopoiesis and leukemogenesis. Bone marrow transplantation assay was performed to explore the function of Elk1 in hematopoiesis under stress conditions. Additionally, bulk-cell RNA sequencing, single-cell RNA sequencing and proteomics were performed to reveal the signaling pathways altered by Elk1. Finally, undifferentiated leukemia cells were used to verify whether inhibiting ELK1 could promote the differentiation of these cells into mature neutrophils.

Results: ELK1 is highly expressed in undifferentiated AML cells. Studies using mouse model demonstrated that overexpression of Elk1 accelerates the development of KrasG12D-induced myeloid leukemia by impairing the stemness of hematopoietic stem cells (HSCs) and impeding the differentiation of neutrophils. Furthermore, impeding the maturation of neutrophils independently promotes the development of KrasG12D mutation-induced myeloid leukemia. Meanwhile, our in vitro experiments preliminarily confirmed that inhibiting ELK1 suppresses the proliferation of leukemia cells and induces the differentiation of CD15⁺CD66b^- myeloid progenitor cells into CD15⁺CD66b⁺ neutrophils.

Conclusions: Our study demonstrates that ELK1 is a potential therapeutic target for AML, due to its critical role in regulating neutrophils differentiation.

The emergence of organoids has received widespread attention for faithful recapitulation of physiological and pathological conditions, together with overcoming the major bottleneck of extrapolating laboratory findings from model systems to human organs. Organoid technologies are one of the most revolutionary breakthroughs in the fields of regenerative medicine and biomedical research. These three-dimensional (3D) micro-organ models are derived from stem cells and tissue derivatives, and can highly simulate the structure and function of parental organs, which thus open up unprecedented avenues for understanding organogenesis, disease modeling, drug screening and individualized therapeutics. In this review, we comprehensively elaborate on the core principles and key elements of organoid construction, and the multidisciplinary integration with the advanced technologies. Simultaneously, we systematically summarize their applications in disease modeling and pharmaceutical research, together with the landscape of organoid-based observational and interventional clinical trials in regenerative medicine. Furthermore, we put forward the outstanding prospects and challenges in organoid-based precise diagnosis and treatment applications. In particular, the long-standing key issues in the field such as vascularization and maturity, standardization and reproducibility, biobank and ethical considerations, and the emerging interdisciplinary integrations. Collectively, we outline the state-of-the-art renewal in organoid-guided precision medicine and regenerative medicine, which will benefit the following investigations in development biology and clinical translation.

Gastric and upper gastrointestinal (GI) oncology is at a point of transformation, with significant advances in each aspect of the disease continuum. Novel clinical tools and therapies, including randomized phase II and III trials, have provided new standards of care for patients, including preoperative chemoradiation for resectable gastric cancer and PD-L1 stratified immuno-chemotherapy in the metastatic setting. Also, many discoveries are co-evolving with newer methods, such as CAR-T therapy or reintroduced microbial undercover agents or burgeoning precision tools. However, obstacles remain, nursing the costs of CAR-T, the paradoxical survival benefit of PD-L1 P146R polymorphism, and other biological ineptitudes along with health system barriers. In this synthesis, we advocate for more closely integrated "bench-to-community" approaches to apply more effective combinations of health population prevention programs, biomarker-guided therapeutics, and omics profiling studies to accelerate and positively impact healthcare practices addressing biological or health system barriers.

Cancer continues to pose a significant issue to public health. Despite the considerable advancements in popular therapies such as surgery, radiation, chemotherapy, targeted therapy, and immunotherapy, a substantial number of patients continue to suffer from cancer due to severe treatment resistance. As a result, it is imperative to have a deeper understanding of the mechanisms behind cancer growth and therapy resistance. Ferroptosis, an iron-dependent form of cell death characterized by excessive lipid peroxidation, has recently been described, attracting heightened interest in its implications in cancer. Ferroptosis offers a new conceptual framework for understanding cancer progression. Some treatments function via regulating ferroptosis, and the tough insensitive to various therapies also involves ferroptosis resistance. Hence, targeting ferroptosis may benefit the cancer treatments. Extracellular vesicles (EVs) are essential mediators in cell-to-cell communications and are significantly impacted by environmental or cellular stress. The relationship between EVs and ferroptosis has recently been steadily demonstrated, and it has also been possible to use EVs to target ferroptosis to treat cancer. We present a novel perspective on cancer by reexamining the existing knowledge of ferroptosis and EVs in this disease. This includes a comprehensive overview of the relationships between ferroptosis and EVs and their therapeutic applications, focusing on contemporary ferroptosis-targeting EVs in the context of cancer.

Introduction: Multiple myeloma (MM) develops in the hypoxic bone marrow (BM) microenvironment, which alters tumor behavior and immune responses. While hypoxia is known to directly suppress immune function, its effect on immunotherapy-relevant antigen expression and the MM secretome remains underexplored. Here, we investigated how hypoxia affects BCMA expression and BCMA-targeted CAR T cell responses.

Methods: MM cells were cultured under normoxia (21% O₂) or hypoxia (1% O₂). BCMA surface and total expression were analyzed. Anti-BCMA CAR T cells were co-cultured with normoxic or hypoxic MM cells to assess cytotoxicity and cytokine release. Conditioned media and small extracellular vesicles (sEVs) were isolated, quantified, and RNA-profiled.

Results: MM cells cultured in hypoxia showed reduced BCMA surface and total protein expression, resulting in reduced CAR-mediated signaling. Importantly, the hypoxic tumor secretome further reduced BCMA levels and significantly impaired CAR T cell killing and cytokine production, which was partially reversible by γ-secretase inhibition. To dissect the suppressive nature of the hypoxic secretome, we identified an increase in small extracellular vesicle (sEV) release under hypoxia. RNA profiling of sEVs revealed a hypoxia-induced RNA signature with potential immunomodulatory roles.

Conclusion: This study shows that hypoxia diminishes BCMA expression and enhances secretion of immunosuppressive factors, including sEVs, thereby limiting the efficacy of BCMA CAR T cell therapy in MM.

Liver pre-metastatic niches (PMN) formation is a pivotal process in colorectal cancer liver metastasis (CLM). Phosphatase of regenerating liver-3 (PRL-3) has been demonstrated as a key factor in promoting CRC progression (e.g., therapeutic resistance and metastasis), but its role in liver PMN formation remains unknown. Using mouse models and CRC patient samples, we herein reveal that high PRL-3 expression in CRC cells could enhance the recruitment of myeloid-derived suppressor cells (MDSCs) into the liver and impair the hepatic infiltration of CD8⁺ T cells, thereby promoting the liver PMN formation and CLM. Mechanistically, high PRL-3 expression could activate the Src/STAT3 signaling pathway in CRC cells and thus up-regulate integrin αvβ5 (ITGαvβ5) expression in their secreted exosomes, which could specifically target F4/80⁺ macrophages in the liver to activate the P38/STAT1 signaling pathway. With this activation of P38/STAT1 pathway, the secretion of C-X-C motif chemokine ligand 12 (CXCL12) from F4/80⁺ macrophages is significantly improved, which could enhance the recruitment of MDSCs into the liver and impair the hepatic infiltration of CD8⁺ T cells, ultimately leading to the liver PMN formation and CLM. Taken together, our findings not only uncover the important role of PRL-3 in CLM via promoting the liver PMN formation, but also provide the evidence for the treatment of CLM by targeting PRL-3.