Experimental Hematology & Oncology最新文献

Background: Triple-negative breast cancer (TNBC) is commonly characterized by high-grade and aggressive features, resulting in an augmented likelihood of distant metastasis and inferior prognosis for patients. Tumor immune microenvironment (TME) has been recently considered to be tightly correlated with tumor progression and immunotherapy response. However, the actual heterogenous TME within TNBC remains more explorations.

Methods: The thorough analyses of different cell types within TME were conducted on the self-tested single-cell RNA sequencing dataset which contained nine TNBC treatment-naïve patients, including subclusters classification, CellChat algorithm, transcription factors (TFs) expression, pseudotime analysis and functional enrichment assay. The malignant epithelial cluster was confirmed by copy number variations analysis, and subsequently LASSO-Cox regression was carried out to establish a Malignant Cell Index (MCI) model on the basis of five crucial genes (BGN, SDC1, IMPDH2, SPINT1, and UQCRFS1), which was validated in several TNBC cohorts through Kaplan-Meier survival and immunotherapy response analyses. The public spatial transcriptome, proteome data and qRT-PCR, western blotting experiments were exploited to corroborate UQCRFS1 expression in RNA and protein levels. Additionally, functional experiments were implemented to unravel the impacts of UQCRFS1 on TNBC cells.

Results: The diverse subclusters of TME cells within TNBC were clarified to display distinct characteristics in cell-cell interactions, TFs expression, differentiation trajectory and functional pathways. Particularly, IL32^high Treg imparted an essential effect on tumor evasion and predicted a worsened prognosis of TNBC patients. Furthermore, MCI model enabled to notify the inferior prognosis and immunotherapy resistance in TNBC. Ultimately, UQCRFS1 knockdown dampened the proliferative and migratory competence in vitro as well as tumor growth in vivo of TNBC cells.

Conclusions: Our study offers innovative perspectives on comprehending the heterogeneity within TME of TNBC, thereby facilitating the elucidation of TNBC biology and providing clinical recommendations for TNBC patients' prognosis, such as IL32^high Treg infiltration, MCI evaluation, and UQCRFS1 expression.

Platelets play a critical role in tumor immunity, particularly in promoting cancer progression. Numerous studies suggest that platelets could serve as a novel target for cancer immunotherapy, however, no comprehensive reviews have yet summarized and discussed this potential. Our review provides an in-depth discussion of the roles and mechanisms of platelets within both the immunosuppressive tumor microenvironment and the anti-tumor immune microenvironment. Additionally, we summarize the key therapeutic targets and approaches for clinical translation. This work offers essential insights for reprogramming platelets to shift their function from tumor promotion to tumor suppression, providing a foundation for the development of novel immunotherapeutic strategies and related research.

Neutrophil extracellular traps (NETs) are complex, web-like structures consisting of DNA intertwined with antimicrobial proteins, which neutrophils release upon immune activation. These structures play a crucial role in pathogen elimination, particularly in infectious diseases. However, their involvement in various pathological conditions is multifaceted and context-dependent, while NETs contribute to host defense against infections, they can also exacerbate sterile inflammation, autoimmune disorders, and tumor progression. This review provides a comprehensive analysis of the molecular mechanisms governing NET formation and examines their interactions with immune cells, emphasizing how these interactions shape immune responses and drive disease dynamics. Furthermore, it explores ongoing clinical trials and emerging therapeutic strategies targeting NETs, offering critical insights into their potential translational applications in clinical practice.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a 5-year overall survival (OS) rate of approximately 12%. More than 90% of PDAC patients harbor oncogenic mutations in the Kirsten rat sarcoma viral homolog (KRAS) gene. MRTX1133 (MRTX), a novel inhibitor of KRAS^G12D (the most common KRAS mutation found in pancreatic and colon cancers) has shown promise as a therapeutic agent. To address reported resistance to MRTX, we adapted our anti-leukemia co-targeting strategy and evaluated a combination of MRTX and Bedaquiline (BED), an FDA-approved inhibitor of mitochondrial ATP production, in in vitro human PDAC models. The combination of MRTX and BED demonstrated enhanced cytotoxic effects by disrupting all 11 genes within the DNA helicase family (CMG complex: CDC45-MCM-GINS), which are essential for initiating DNA replication and regulating cell cycle progression. Notably, real-world data analysis from Caris Life Sciences and NCI-TCGA database revealed that low transcriptomic expression of the DNA helicase CMG complex was significantly associated with prolonged survival (e.g., low CDC45 expression and low GINS2 expression with greater than 8 months longer overall survival) in PDAC patients with KRAS^G12 mutations (N = 9,717; P < 0.00001). However, this combination therapy also triggered strong pro-survival nuclear reprogramming. This effect was mediated by significant genetic activation of an NFκB2-DDIT (DNA damage-induced transcript) axis, which supported tumor chromosomal integrity and DNA repair mechanisms. To overcome NFκB2-driven resistance mechanisms, we explored a triple-targeting strategy that addresses metabolic and genomic plasticity in addition to actively intercepting cell division. This approach combines MRTX1133, Bedaquiline, and the NFκB2 inhibitor SN52, offering a novel therapeutic avenue to treat aggressive pancreatic cancer and potentially improve patient outcomes.

Menin inhibitors (MENINis) represent a novel and promising class of therapeutic agents for acute leukemia (AL). AL subtypes driven by overexpressed HOXA9/MEIS1, such as those characterized by KMT2A-rearranged (KMT2Ar) or NPM1-mutated (NPM1m) AL, display sensitivity to MENINi. Consequently, approximately 40-50% of acute myeloid leukemia (AML) and 5-15% of acute lymphoblastic leukemia (ALL) patients may potentially benefit from MENINi-based therapy. At the 2024 ASH annual meeting, updated clinical data regarding monotherapy with MENINis in AL, including revumenib, bleximenib, enzomenib and BN104, were presented. Moreover, combination therapies based on MENINis were also reported to be highly effective in refractory/relapsed, or newly diagnosed KMT2Ar- and NPM1m-AML patients. Evidently, MENINis have demonstrated a considerable efficacy in KMT2Ar- and NPM1m-AML patients with a well-tolerance. Furthermore, the therapeutic effects of venetoclax plus azacitidine or "3 + 7" regimens were further enhanced by the addition of MENINis in KMT2Ar- and NPM1m-AML patients. Therefore, MENINis offer new therapeutic prospects for AML patients, particularly for those with high-risky and poor-prognostic on-target subtypes.

Breast cancer remains one of the most prevalent malignancies worldwide, underscoring an urgent need for innovative therapeutic strategies. Immunotherapy has emerged as a transformative frontier in this context. In triple-negative breast cancer (TNBC), the combination of immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors (ICIs) with chemotherapy has proven efficacious in both early and advanced clinical trials. These encouraging results have led to the approval of ICIs for TNBC, opening up new therapeutic avenues for challenging-to-treat patient populations. Furthermore, a multitude of ongoing trials are actively investigating the efficacy of immunotherapy-based combinations, including ICIs in conjunction with chemotherapy, targeted therapy and radiation therapy, as well as other novel strategies such as bispecific antibodies, CAR-T cells and cancer vaccines across all breast cancer subtypes, including HR-positive/HER2-negative and HER2-positive disease. This review provides a comprehensive overview of current immunotherapeutic approaches in breast cancer, highlighting pivotal findings from recent clinical trials and the potential impact of these advancements on patient outcomes.

Nanotechnology has revolutionized cancer therapy by introducing advanced drug delivery systems that enhance therapeutic efficacy while reducing adverse effects. By leveraging various nanoparticle platforms-including liposomes, polymeric nanoparticles, and inorganic nanoparticles-researchers have improved drug solubility, stability, and bioavailability. Additionally, new nanodevices are being engineered to respond to specific physiological conditions like temperature and pH variations, enabling controlled drug release and optimizing therapeutic outcomes. Beyond drug delivery, nanotechnology plays a crucial role in the theranostic field due to the functionalization of specific materials that combine tumor detection and targeted treatment features. This review analyzes the clinical impact of nanotechnology, spanning from early-phase trials to pivotal phase 3 studies that have obtained regulatory approval, while also offering a critical perspective on the preclinical domain and its translational potential for future human applications. Despite significant progress, greater attention must be placed on key challenges, such as biocompatibility barriers and the lack of regulatory standardization, to ensure the successful translation of nanomedicine into routine clinical practice.