Experimental Hematology & Oncology最新文献

Collagen in the tumor microenvironment plays diverse biological roles, from serving as the structural framework of tumors to influencing immune responses, angiogenesis, and tumor progression. Consequently, developing strategies to optimize the suppression of collagen's promotive effects on tumor growth while maintaining its inhibitory functions on tumor initiation has become a key focus of cancer research and therapy. A significant challenge remains in identifying a biomarker with both high sensitivity and specificity for cancer diagnosis. This review, therefore, highlights the substantial value and clinical relevance of collagen as a biomarker throughout cancer onset and progression. It explores the fundamental link between collagen and immunotherapeutic outcomes, further illustrating how targeting collagen-along with its interactions with tumors and immune cells-can offer more reliable predictive markers for personalized immunotherapy. This approach ultimately enables the development of more tailored and standardized treatment regimens for patients with cancer.

Dysfunction of cytotoxic T cells (CTL) remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that increased soluble form of ICOSL (sICOSL) induced CTL dysfunction and was associated with shorter survival of patients with breast cancer. sICOSL emerged as a formidable adversary to CTLs, by directly triggering ICOS internalization and subsequent degradation-a critical blow to the co-stimulatory machinery essential for CTL activation. Our research shows that dipeptidyl peptidase-4 (DPP4) mainly breaks down sICOSL. Notably, certain chemotherapeutic drugs activate the histone methyltransferase Enhancer of zeste homolog 2 (EZH2), which in turn suppresses DPP4 expression. To address this issue, we have developed nanobody-DPP4 fusion proteins that can specifically degrade sICOSL, achieving substrate selectivity and tumor targeting. Overall, This work unveils that sICOSL orchestrates CTL dysfunction, and establishs targeted degradation of sICOSL as a new strategy for immunotherapy.

The tumor microenvironment (TME) represents a metabolic battleground where immune cells and cancer cells vie for essential nutrients, ultimately influencing antitumor immunity and treatment outcomes. Recent advancements have shed light on how the metabolic reprogramming of immune cells, including macrophages, T cells, and DCs, determines their functional polarization, survival, and interactions within the TME. Factors such as hypoxia, acidosis, and nutrient deprivation drive immune cells toward immunosuppressive phenotypes, while metabolic interactions between tumors and stromal cells further entrench therapeutic resistance. This review synthesizes new insights into the metabolic checkpoints that regulate immune cell behavior, focusing on processes like glycolysis, oxidative phosphorylation (OXPHOS), lipid oxidation, and amino acid dependencies. We emphasize how metabolic enzymes (e.g., IDO1, ACLY, CPT1A) and metabolites (e.g., lactate, kynurenine) facilitate immune evasion, and we propose strategies to reverse these pathways. Innovations such as single-cell metabolomics, spatial profiling, and AI-driven drug discovery are transforming our understanding of metabolic heterogeneity and its clinical implications. Furthermore, we discuss cutting-edge therapeutic approaches-from dual-targeting metabolic inhibitors to biomaterial-based delivery systems-that aim to reprogram immune cell metabolism and enhance the effectiveness of immunotherapy. Despite the promise in preclinical studies, challenges persist in translating these findings to clinical applications, including biomarker validation, metabolic plasticity, and interpatient variability. By connecting mechanistic discoveries with translational applications, this review highlights the potential of immunometabolic targeting to overcome resistance and redefine precision oncology.

Mesenchymal stem/stromal cells (MSCs) possess significant potential in regenerative medicine, attributed to their inherent capacity for site-specific homing to inflammatory regions, diverse differentiation abilities, and immunomodulatory functions. Tumors represent a substantial threat to human health, and therapeutic options remain limited. The inherent ability of MSCs to migrate towards tumor sites has been extensively utilized in cancer therapies. However, MSCs have shown ambiguous effects on tumors and contribute to the tumor microenvironment by trans-differentiation into different stromal cell types. Tumor-associated MSCs (TA-MSCs), derived from various tumor tissues, have been identified for their role in promoting tumor progression by interacting with tumor cells and other stromal components. As integral components of the tumor stroma, TA-MSCs provide a novel perspective for elucidating the mechanisms underlying malignancy. This review enhances our comprehension of TA-MSCs in solid tumors by summarizing evidence on their existence, differences from normal MSCs, heterogeneity, and roles in tumor initiation and progression. Furthermore, this review underscores the potential clinical implications of TA-MSCs for tumor diagnosis, prognosis prediction, and therapy.

Background: Hematologic malignancies are one of the most common types of cancer. This study aims to assess the global burden of hematologic malignancies and analyze the global epidemiological trends.

Methods: Through the Global Burden of Disease Study 2021 (GBD 2021) and the Global Cancer Observatory (GLOBOCAN) 2022 project, we comprehensively evaluated the global prevalence, incidence, mortality, and disability-adjusted life-years (DALYs) of seven major hematologic malignancies, as well as their respective age-standardized rates (ASR) per 100,000 population. Regions were classified using the Socio-demographic Index (SDI) to evaluate the correlation between disease burden and economic level. In addition, we analyzed disease-related risk factors and predicted future trends up to 2040.

Results: From 1990 to 2021/2022, the number of global hematologic malignancy cases showed a continuously increasing trend, especially for non-Hodgkin lymphoma. However, the age-standardized death rates (ASDR) and age-standardized DALY rates (ASDALYR) of all types of hematologic malignancies tended to be stable or decline. For acute lymphoblastic leukemia, the number of death cases, ASDR, and ASDALYR decreased significantly. Nevertheless, the trends of hematologic malignancies varied by gender, age, and SDI. The burden of hematologic malignancies was generally higher in the elderly and male populations. Of course, acute lymphoblastic leukemia also imposed a huge burden on children, Hodgkin lymphoma also significantly burdened young people. Moreover, regions with a higher SDI had a higher incidence rate. Deaths related to smoking and high body mass index still played an important role in various regions, especially in regions with a higher SDI. It is predicted that the global age-standardized incidence rates (ASIR) and ASDALYR will show a slow downward trend by 2040.

Conclusions: Hematologic malignancies have remained a major global public health issue, with significant demographic and regional differences. The results of this study will provide a basis for analyzing the trends of the global disease burden of specific hematologic malignancies and offer a reference for health policymakers.

Antibody-drug conjugates (ADCs) represent a promising therapeutic strategy for non-small cell lung cancer (NSCLC), targeting tumor-specific antigens with precision. However, the molecular heterogeneity of NSCLC necessitates multiplex biomarker approaches to optimize ADC efficacy. This study utilized transcriptomics and proteomics to characterize NSCLC subtypes with distinct ADC target expression profiles. RNA-seq data from two independent cohorts (537 tumors, 59 controls; 338 tumors, 311 controls) identified clusters defined by overexpression of CEACAM5, MET, and TACSTD2, while normal lung tissue exhibited moderate TACSTD2 and FOLR1 expression. Chi-squared residual analysis revealed no significant associations with disease stage or driver mutations. Proteomic and transcriptomic data from 110 tumors and 101 controls demonstrated strong concordance. These findings highlight the potential of ADCs to target NSCLC subsets with distinct proteogenomic profiles, independent of disease stage or mutational status, underscoring their broad applicability in precision oncology.

Background: Our open-label, multicenter, randomized, phase 3 trial showed that the incidence and severity of chronic graft-versus-host disease (cGVHD) reduced in steroid-resistant acute graft-versus-host disease (aGVHD) patients who underwent mesenchymal stromal cells (MSCs) treatments, but survival benefit was not received. Here, we present a post-hoc analysis of the 5-year follow-up to explore long-term survival and its underlying mechanism.

Methods: This long-term follow-up trial included steroid-resistant aGVHD patients, who were randomly assigned (1:1) to receive MSCs (MSC group) (1 × 10⁶ cells/kg once weekly for 4 consecutive weeks, 8 doses at most) or without MSCs treatment (control group). For this updated analysis, the 5-year endpoints were cumulative incidence of cGVHD, overall survival, cGVHD-free, relapse-free survival (CRFS), and relapse. To explore the mechanism, We investigated the changes in T, B cells, and signal joint T cell receptor excision DNA circles (sjTRECs).

Results: Between September 2014 and March 2019, 198 patients were randomly assigned to the MSC group (n = 99) or the control group (n = 99). Extended follow-up showed the lower 5-year cumulative incidence of cGVHD (42.0% [95%CI 32.2-51.5] vs. 67.1% [55.6-76.3]; hazard ratio [HR] 2.19, 95%CI 1.47-3.27; P < 0.001), improved 5-year overall survival (60.4% [50.8-70.0] vs. 41.7% [31.9-51.5]; 0.63, 0.42-0.94; P = 0.023), CRFS (33.9% [24.5-43.3] vs. 20.9% [12.9-28.9]; 0.67, 0.48-0.93; P = 0.017) and no increase on relapse (13.6% [7.6-21.3] vs. 16.0% [9.5-23.9]; 1.24, 0.60-2.56; P = 0.568) for patients in MSC group compared with the control group. Clinical improvement of MSCs was accompanied by significant increases in regulatory T cells, CD4 + CD45RA + CD31 + naïve T, CD19 + CD27 + IgD- memory B cells, and sjTRECs.

Conclusions: With extended follow-up, MSCs reduced the morbidity of cGVHD in aGVHD patients and improved overall survival and CRFS. Mechanistically, MSCs reduced cGVHD by thymus pathway.

Trial registration: clinicaltrials.gov identifier: NCT02241018. Registration date: 16 September 2014, https://clinicaltrials.gov/ct2/show/NCT02241018 .

Lung cancer is a major malignant tumor with high morbidity and fatality rates. For many years, traditional treatments for lung cancer have struggled to achieve a favorable outlook and prognosis. It is crucial to identify and innovate novel clinical therapeutic strategies and techniques to prevent tumor progression and prolong the survival time of patients with lung cancer. Cellular immunotherapies have revolutionized the treatment of malignant tumors and have been gradually applied in clinical practice. CAR-T therapy is the best-known cellular therapy and has achieved remarkable clinical outcomes in patients with hematological malignancies, but its effect on patients with lung cancer and other solid tumors is not satisfactory, partly because of the heterogeneity and complexity of lung cancers and the sterile TMEs. To further improve the clinical effect, multiple approaches and strategies have been adopted, including discovering new tumor antigen targets, improving safety, enhancing cytotoxicity, and increasing durability. Moreover, other cell-based immunotherapies have also showed great potential for the treatment of lung cancer, including TCR-T cells, TILs, CIK cells, NK cells, macrophages, and dendritic cells, which enriched the number of treatment choices for patients with lung cancer. In summary, the present article summarizes and highlights recent advances and challenges in the use of cellular immunotherapies for the treatment of lung cancer, which might stimulate new ideas for the further development of cellular immunotherapies.

CD226 plays a vital role in NK cell cytotoxicity, interacting with its ligands on tumor targets. Acute myeloid leukemia (AML) cells have developed mechanisms to escape NK cell cytotoxicity, including inducing downregulation of CD226 on NK cells. Induced pluripotent stem cell -derived NK (iPSC-NK) cells offer an important source of standardized off-the-shelf NK cell therapy to treat AML patients. In this study, we engineered iPSC-NK cells with CD226 to assess the ability of killing AML cells. iPSC-NK cells engineered with CD226 have a typical NK cell phenotype and demonstrate improved anti-AML activity and multiple cytokines releasing at low effector-to-target ratios. Transcriptomic analysis revealed upregulation of immune effector function pathways associated with cytotoxicity and immune activation in CD226-overexpression iPSC-NK cells. In an AML xenograft model, mice treated with CD226 overexpression iPSC-NK cells exhibited significantly reduced leukemia burden, prolonged survival, decreased systemic inflammation compared to those treated with Control iPSC-NK cells. Overall, our study provided evidence that iPSC derived-NK cells engineered with CD226 represent a promising candidate for off-the-shelf immunotherapy, particularly in AML and other CD226 ligand-expressing malignancies.

Chimeric antigen receptor (CAR) engineered cellular immunotherapy offers the potential for precise targeting and elimination of tumor cells, providing a tailored approach to cancer treatment. CAR-T cells demonstrate significant anti-tumor activity among these therapies. Nonetheless, these therapies may trigger adverse effects, including inflammatory and neurotoxic reactions during treatment. Recent efforts have been directed toward enhancing efficacy by optimizing CAR design or modulating its activity. Compared to CAR-T cells, CAR-engineered natural killer cells (CAR-NK) present notable advantages, including various sources and diminished toxicity, and are gaining recognition in clinical research. CAR-macrophages (CAR-M), while sharing antigenic domains similar to those of CAR-T cells, display superior capabilities in antigen presentation and tumor penetration. As a result, there is significant enthusiasm surrounding investigations into CAR-NK and CAR-M cell immunotherapies. This review explores the existing environment and obstacles associated with immunotherapies that utilize CAR-T, CAR-NK, and CAR-M cells to inspire novel pathways for forthcoming clinical applications.