Experimental Hematology & Oncology最新文献

While CAR-T cell therapy has been very successful for treating B cell malignancies, and more recently multiple myeloma, achieving clinical success for acute myeloid leukemia (AML) remains a significant challenge. The examination of current single-antigen targeting CAR-T cell studies for AML illustrates the challenges faced by this therapy: efficacy limitations arise from the heterogeneity of the disease, which often results in antigen escape and subsequent circumvention of single-antigen targeting CAR-T cells, while safety limitations are mainly due to undesired hematological toxicity stemming from the absence of an antigen specifically expressed on AML tumor cells and not on normal hematopoietic cells. This study offers a comprehensive analysis of the most relevant AML surface antigenic markers -CD123, CD33, ADGRE2, CLL-1, TIM-3, CD70, among others- along with their expression patterns across key cell types, including leukemic blasts, leukemic stem cells, hematopoietic stem cells and progenitors, adult blood cells, and other tissues. Additionally, a variety of strategies for developing CAR-T therapies with improved efficacy and specificity are explored, with dual-antigen targeting CAR-T cell therapies emerging as the most promising approach to overcome the major hurdles observed in single-antigen targeting CAR-T cell therapies. Overall, this review identifies dual-antigen targeting as a therapy holding great prospects in the search of an effective and safe therapeutic approach for AML patients.

The development of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment represents a significant challenge to targeted therapies for lung cancer. To explore the feasibility of epigenetic therapy in overcoming resistance, an epigenetic drug library was screened, identifying Remodelin as a potent enhancer of EGFR-TKI sensitivity in non-small cell lung cancer (NSCLC) cells. We demonstrated that the cytidine acetyltransferase NAT10 was overexpressed in NSCLC tissues and was associated with poor patient prognosis. NAT10 knockdown inhibited proliferation, increased apoptosis, and enhanced sensitivity to EGFR-TKIs both in vitro and in vivo. Mechanistically, NAT10 promoted EGFR-TKI resistance in NSCLC by remodeling fatty acid metabolism. Specifically, NAT10 was found to promote ac4C modification of fatty acid transport protein 4 (FATP4) and carnitine palmitoyltransferase 1 A (CPT1A) mRNAs, leading to increased stability and expression of these genes. Furthermore, p300-mediated H3K27ac acetylation was found to be a critical upstream regulator of NAT10 transcription. In vivo, mouse xenograft models confirmed that Remodelin significantly enhanced the antitumor efficacy of gefitinib. These findings suggest the potential of NAT10 as a therapeutic target to overcome EGFR-TKI resistance and improve treatment outcomes in patients with NSCLC.

Background: Malignant ascites (MA) is one of the major complications in advanced epithelial cancer patients and is associated with poor prognosis, poor quality of life, and severe symptoms. No efficient medicine is available for treating MA worldwide. Only paracentesis is recommended by the guidelines in most countries, but with limited efficacy and a short control time. Thus, novel treatments are needed to control MA.

Methods: An anti-EpCAM × anti-CD3 bispecific antibody, M701, was constructed as a T-cell engager to eliminate tumor cells in the peritoneal cavity. A phase II study was performed to evaluate the efficacy and safety of the intraperitoneal (IP) infusion of M701 in advanced epithelial tumor patients with moderate-to-large-scale MA. In this study, 84 patients were enrolled, with 43 in the M701 group receiving paracentesis and IP M701 infusion and 41 in the control group receiving paracentesis alone.

Results: The primary endpoint, median puncture-free survival (PuFS), was 75 days in the M701 group and 25 days in the control group, with a significant difference (p = 0.0065). Subgroup analysis indicated that different types of cancer, including gastric, colorectal, and ovarian cancers, all benefited from the M701 infusion. Patients with higher relative lymphocyte counts (≥ 13%) at baseline received better effects. Compared to patients in the control group, the overall survival (OS) of patients in the M701 group was certain extended (mOS 110 days vs. 76 days, p = 0.1443, HR = 0.68). The 6-month survival rates were 33.3% and 12.1% in the two groups, respectively. No additional serious adverse events (SAEs) were detected in the M701 group. The most frequent treatment-related adverse events were anemia and low white blood cell count, which were manageable. M701 infusions did not cause a greater risk than paracentesis alone in the control arm, while all patients were administered systemic treatment.

Conclusion: When treated with M701, patients with MA had significantly longer puncture intervals and a trend of extended survival time. The results were encouraging for patients with MA. A phase III clinical trial of M701 aimed at further validation is ongoing.

After decades of development and accumulation, chimeric antigen receptor (CAR)-T therapy has become a revolutionary immunotherapy method, which has triggered changes in treatment methods and concepts in the fields of cancer, autoimmune disorders, infection, fibrosis and other diseases. With the continuous expansion of indications and potential application fields, adoptive CAR-T therapy products are difficult to meet the expanding market demand and provide equal access to treatment due to their technical complexity and substantial production costs. These factors drive the development and practice of novel technologies, in this context, in vivo CAR-T therapy has been proposed: the in vivo or in situ programming of CAR-T cells to eliminate pathological cells through the delivery of CAR genes in vivo by viruses or engineered nanoparticles. This new technology pathway simplifies the manufacturing and therapeutic procedures, reduces treatment costs, and improves patient accessibility, which has excellent potential for clinical application. This article reviews recent advances in in vivo CAR-T therapy, compares the advantages and characteristics of this approach with traditional adoptive therapy, discusses the therapeutic risks and related challenges of in vivo CAR-T therapy, and emphasizes the guiding significance of adoptive therapy-based enhancement strategies for the development of in vivo CAR-T therapy.

Background: Current therapeutic strategies for endometrial cancer are mainly based on aggressive histological types and molecular subtypes. However, ignoring the spatial distribution of immune/stromal cells fails to account for the heterogeneity of the local tumour microenvironment, leading to biased prediction of treatment response. The goal of precision medicine is to delineate the biological characteristics of local functional units based on molecular labelling, which adequately reflects spatially adaptive changes during treatment or metastasis.

Methods: Single-cell resolution analysis of 40 endometrial cancer cases across four molecular subtypes was performed using imaging mass cytometry (IMC) to quantify the frequency, spatial distribution, and intercellular crosstalk of distinct immune and stromal cell populations. These ecosystem-level features were systematically correlated with clinical features and outcomes, including treatment response and survival. We further identified CD90 + clusters as key regulators of macrophage polarization and T-cell infiltration dynamics, with flow cytometry used to validate their functional role in tumour subtype specification and microenvironmental remodelling. Finally, machine learning-based spatial phenotyping was employed to construct molecular subtype-specific signatures and a highly accurate recurrence prediction model for high-risk endometrial cancer.

Results: Single-cell profiling revealed that CD90 + clusters constitute a critical immunomodulatory component within the tumour microenvironment, demonstrating significant enrichment in macrophage differentiation pathways and serving as key mediators of intercellular signalling networks. Furthermore, computational models integrating functional molecular signatures with cell-cell interaction profiles demonstrated high predictive accuracy for both molecular subtyping and recurrence risk stratification in patients with endometrial carcinoma.

Conclusions: Our study establishes a spatial eco-context framework for molecular subtypes of endometrial cancer by integrating single-cell spatial multiomics data. This approach enables high-resolution mapping of tumour-immune-stromal interaction networks and reveals novel targets for personalized therapeutic strategies.

In addition to their central role in blood hemostasis, it is increasingly clear that platelets contribute to multiple steps in the metastatic cascade. Platelets are one of the most abundant cells with which tumor cells interact once they enter the circulation, and the interaction of platelets with tumor cells can improve tumor cell survival, arrest and adhesion at secondary sites, and extravasation. Therefore, targeting the interaction between platelets and circulating tumor cells could be an effective approach for reducing metastasis. Here, we repurpose the thromboxane A₂-prostanoid receptor (TPr) inhibitor, ifetroban, to block platelet-tumor cell interactions and reduce metastasis in models of triple negative breast cancer (TNBC). We utilize in vitro co-culture models of platelets and tumor cell lines to assess the impact of ifetroban treatment on the adhesion of platelets to tumor cells. In each case, platelet-tumor cell adhesion was significantly increased when the TPr agonist U46619 was introduced, while pre-treatment with ifetroban (TPr antagonist), significantly reduced platelet-tumor cell adhesion. Further, we used a zebrafish model system to rapidly assess metastasis and platelet interactions in vivo, showing that ifetroban reduces metastasis of MDA-MB-231 xenografts without reducing platelet number in CD41 transgenic zebrafish embryos. Finally, we confirm that ifetroban significantly reduces both lung and liver metastasis in multiple murine models of TNBC (4T1 and MDA-MB-231). In these models, we observed that ifetroban reduces metastasis in the absence of a primary tumor and when TPr is deleted from tumor cells, further supporting the notion that ifetroban attenuates the supportive role of platelet TPr in the metastatic cascade. Based on the results of this study, ifetroban could be pursued as a clinical agent to reduce metastasis in TNBC patients.

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with limited treatment options. While immunotherapy has revolutionized SCLC therapy and now serves as a front-line treatment, the disease continues to present significant clinical challenges. Despite therapeutic advances in lung cancer over the past decade, most SCLC tumors eventually reoccur. Growing insights into the tumor-immune microenvironment (TIME) highlights its critical role in SCLC progression and therapeutic resistance. In this review, we summarize distinctive features of the TIME in SCLC and evaluate current immunotherapeutic strategies, notably immune checkpoint inhibitors (ICIs), that have demonstrated survival benefits in a subset of patients. Furthermore, we explore emerging immunotherapeutic approaches and novel targets in SCLC, emphasizing the challenges limiting the successful application of immunotherapy in this disease.

Lactate, a key metabolite of the Warburg effect, plays a central role in shaping multiple hallmarks of cancer. Through lactate shuttling and engagement with specific receptors, it activates downstream signaling pathways that remodel the tumor microenvironment (TME) and facilitate tumor progression. More recently, lysine lactylation-an emerging post-translational modification derived from lactate-has been identified as a crucial epigenetic mechanism that links altered tumor metabolism with transcriptional regulation. Lactylation has been implicated in promoting tumor proliferation, metastasis, stemness maintenance, immune evasion, and therapeutic resistance across various cancer types. Both tumor and immune cells undergo lactylation, which modulates gene expression and contributes to the immunosuppressive landscape of the TME. Targeting lactate production and transport has shown promise in suppressing tumor growth and enhancing immunotherapeutic efficacy. In this review, we comprehensively discuss the functional roles and underlying mechanisms of lactate and lactylation in cancer progression, with a particular focus on their impact within the TME. We also highlight recent advances in targeting these metabolic processes as potential therapeutic strategies, aiming to provide new perspectives for improving cancer treatment outcomes.

Reconstructing and understanding intra-tumor heterogeneity, the coexistence of multiple genetically distinct subclones within the tumor of a patient, and tumor development is essential for resolving carcinogenesis and for identifying mechanisms of therapy resistance. While bulk sequencing can provide a broad view on tumoral complexity/heterogeneity of a patient, single-cell analysis remains essential to identify rare subclones that might drive chemotherapy resistance. In this study, we performed an integrated analysis of bulk and single-cell DNA sequencing data of core-binding factor acute myeloid leukemia patients, defined by the presence of a RUNX1::RUNX1T1 or CBFB::MYH11 fusion gene. By single-cell sequencing, we inferred tumor phylogenies for 8 patients at diagnosis including patient-specific somatic variants, somatic copy-number alterations and fusion genes, and studied clonal evolution under the pressure of chemotherapy for 3 patients. As a result, we developed an approach to reliably integrate subclonal somatic copy number alterations into phylogenetic trees and clonal evolution analysis, obtaining unprecedented resolution of intra-tumor heterogeneity in CBF AML. We were able to show that the fusion gene is among the earliest events of leukemogenesis at single-cell level. We identified remaining tumor clones in 6 patients with complete remission samples indicating incomplete eradication of the tumor clones. Here, we show that identifying the order of mutation acquisition can provide valuable insights into evolutionary history, offering a framework to improve drug selection in the era of targeted therapies.