Experimental Hematology & Oncology最新文献

Remarkable progress has been made in cancer immunotherapy in recent years; however, it still faces challenges such as limited response rates, resistance, and immune-related adverse events. Ubiquitination, a key post-translational modification (PTM) of proteins, is indispensable for regulating various tumor immunity-related processes. Through the dynamic balance between ubiquitin ligases and deubiquitinases, this PTM fine-tunes the strength and duration of immune responses, influencing tumor recognition and immune evasion. Accumulating evidence reveals that ubiquitination does not act alone but cooperates and competes with other PTMs-such as phosphorylation, acetylation, SUMOylation, neddylation, and glycosylation-to form a multilayered regulatory network that determines the immune landscape and therapeutic responsiveness. This review systematically summarizes the molecular mechanisms by which ubiquitination-related enzymes modulate the tumor immune microenvironment and immune evasion. Moreover, we highlight emerging insights into the crosstalk between ubiquitination and other PTMs, which collectively govern the stability and signaling of immune regulators. Finally, we discuss the translational potential of targeting the ubiquitin system, emphasizing opportunities and challenges in developing selective ubiquitin modulators and designing rational combination immunotherapies. Decoding this integrated PTM network will not only deepen mechanistic understanding of tumor immunity but also open new avenues for precision immunotherapy.

Despite the clinical success of T cell-based immunotherapies such as CAR-T cells and bispecific T cell engagers (BiTEs), therapeutic resistance and immune suppression remain significant barriers in B-cell malignancies. To address these, we developed a novel dual-functional extracellular vesicle (EV) platform, termed BiTE EV@STA, that displays anti-CD3/CD19 BiTE molecules on the EV surface while encapsulating a STING agonist (STA). This strategy enables simultaneous redirection of cytotoxic T cells to tumor cells and stimulation of innate immunity within the tumor microenvironment (TME). BiTE EVs demonstrated favorable pharmacokinetics, enhanced tumor targeting, and robust T cell dependent cytotoxicity and cytokine release. In Nalm6-Luc xenograft models, BiTE EVs significantly inhibited tumor progression and prolonged survival. Further loading of STING agonists into EVs (BiTE EV@STA) activated dendritic cells, and enhanced CD8⁺ T cell infiltration in the TME. Notably, BiTE EV@STA achieved a 4-fold increase in tumor growth inhibition and a marked survival benefit compared to either component alone. This study presents BiTE EV@STA as a promising EV-based immunotherapy that integrates adaptive and innate immune activation to overcome TME-mediated resistance. These findings may have broad implications for enhancing T cell-based therapies in hematologic malignancies and beyond.

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest cancers, with limited surgical eligibility, modest chemotherapy benefit, and resistance to immune checkpoint blockade. Two recent vaccine platforms have shown encouraging results. Wainberg et al. demonstrated that the amphiphile vaccine ELI-002 efficiently traffics to lymph nodes via albumin binding and induced KRAS-specific T-cell responses in most patients, correlating with survival. In parallel, Sethna et al. reported that an individualized uridine-modified mRNA vaccine elicited durable, polyfunctional CD8⁺ T cells with long-term persistence, especially when combined with PD-1 blockade. Amphiphiles provide rapid and efficient priming, whereas mRNA vaccines broaden and sustain clonotypic diversity. A hybrid prime-boost strategy may synergize these complementary mechanisms, while advances in multi-omics and AI-driven neoantigen prediction pave the way for personalized designs. Together, these developments suggest that PDAC, long regarded as immunologically "cold," may become tractable to vaccination strategies. Importantly, these findings are based on early-phase clinical studies with limited patient numbers and should therefore be interpreted as preliminary clinical evidence requiring further studies.

Superficial spreading melanoma (SSM) and nodular melanoma (NM) are the two histotypes that account for most cutaneous primary melanomas. We evaluated the mutational status for the genes underlying melanomagenesis among a series of SSMs and NMs from different Italian geographical areas. An increased number of mutated melanoma-driver genes was found to occur in both histological subtypes, with no specific mutational pattern distinctive for SSM and NM lesions, being significantly associated to shorter progression-free survival and poorer overall survival.

The intricate crosstalk between the nervous system and tumors has emerged as a pivotal determinant of tumorigenesis, progression, and therapeutic response. This review synthesizes current insights into neuro-tumor interactions, highlighting how neuronal networks within the tumor microenvironment (TME) modulate cancer cell proliferation, invasion, and angiogenesis by releasing neurotransmitters, growth factors, etc. The neuro-immune axis, a critical interface linking neural signaling to immune regulation, is explored in depth, elucidating how neuronal-derived molecules influence the phenotype and function of immune cells (e.g., T cells, macrophages, natural killer (NK) cells) to affect anti-tumor immunity. In addition, the review also addresses neurotoxicity associated with tumor progression, particularly tumor-induced neuropathic pain, which arises from treatment-related injury. Finally, the therapeutic potential of targeting neural components in cancer is evaluated, including strategies to disrupt neuro-tumor communication (e.g., neurotransmitter receptor antagonists), modulate neuro-immune crosstalk, and alleviate treatment-related neurotoxicity. Overall, this review underscores the need to integrate neural signaling pathways into cancer biology and therapy, identifying unresolved issues in neuro-oncology and highlighting promising directions for developing neuro-targeted interventions to improve patient outcomes.

The tumor microenvironment (TME) in breast cancer is shaped by reciprocal interactions between cancer cells and their surrounding stromal populations. Here, we show that breast adipose tissue-derived stromal/stem cells (bASCs) undergo distinct state transitions in response to tumor cues and systemic metabolic status. Using primary bASCs derived from tumor-adjacent and tumor-distant adipose tissues of breast cancer patients with or without obesity, we identify two functionally distinct, tumor-educated stromal phenotypes: a cytokine-rich inflammatory CAF-like (iCAF) state predominating in lean-adjacent bASCs (ln-aT), and a myofibroblastic CAF-like (myCAF) state emerging in obese-adjacent bASCs (ob-aT). Importantly, transforming growth factor β (TGFβ) is sufficient to induce myCAF-like reprogramming in obesity-primed bASCs, while interleukin 1 (IL1)-Janus kinase (JAK) signaling promotes iCAF features. Re-analysis of single-cell RNA-seq data of breast cancer samples reveals an increased TGFβ expression across stromal and immune cell types in individuals with obesity. Mechanistically, IL1 receptor blockade (anakinra) or JAK inhibition (AZD1480) reverses both iCAF and myCAF phenotypes and functionally suppresses stromal-driven epithelial-mesenchymal transition as well as cancer stemness in breast cancer cells. These findings establish a mechanistic link between obese cues, stromal plasticity, and breast cancer progression, and reveal IL1/JAK signaling as a tractable axis to therapeutically reprogram the breast cancer stroma.

Background: TP53-mutated acute myeloid leukemia (AML) represents one of the most adverse-risk subtypes of AML, yet the mechanisms underlying its resistance and relapse remain poorly defined.

Methods: We performed single-cell RNA sequencing on bone marrow samples from 30 de novo AML patients (11 TP53-mutated, 19 TP53-wild-type) and systematically analyzed leukemic, immune, and stromal compartments to delineate differentiation trajectories, transcriptional heterogeneity, and microenvironmental remodeling. We also performed in vitro assays to validate ferroptosis resistance, leukemia-T cell dysfunction, and stromal remodeling suggested by the single-cell data.

Results: TP53-mutated AML exhibited a differentiation bias toward granulocyte-monocyte and late myeloid progenitors rather than arrest at the stem cell stage, with enhanced anti-apoptotic and inflammatory programs and a transcriptionally and functionally supported ferroptosis resistance phenotype as a novel hallmark linked to poor prognosis. Functionally, CD8⁺ T cells were predominantly exhausted with an enrichment of dysfunctional subsets and a concomitant reduction of NK cells. B cells showed impaired activation with skewed plasma cell composition, and myeloid cells acquired immunosuppressive features. In the stromal compartment, mesenchymal cells lost hematopoietic and immune-supportive functions and shifted toward osteogenic programs, further reinforcing leukemic survival. We also established an integrated ecosystem score that, together with TP53 mutation burden and mono- versus multi-hit status, captured prognostic heterogeneity and enabled clinical stratification.

Conclusions: This study provides the first single-cell landscape of de novo TP53-mutated AML, highlighting its reprogrammed leukemic hierarchy and disrupted immune-stromal ecosystem, and offering mechanistic insights and potential therapeutic targets for this high-risk subtype.

Background: Aggressive subtypes of uterine endometrial carcinoma (UEC) often result in mortality due to recurrence of disease with chemoresistant tumor cells surrounded by an immune suppressive microenvironment. Current CAR-T cell therapies have shown limited efficacy in solid tumors, largely constrained by poor tumor infiltration, immune suppression, and the logistical limitations of autologous cell production, which hinder broad patient access.

Methods: In this study, we conducted comprehensive immunophenotyping of primary UEC patient samples and identified a therapeutic opportunity for CAR-engineered invariant natural killer T (CAR-NKT) cells capable of targeting both tumor cells and the immunosuppressive TME. Using a hematopoietic stem and progenitor cell (HSPC) engineering platform coupled with ex vivo differentiation culture, we generated allogeneic mesothelin-targeting CAR-NKT cells (^AlloMCAR-NKT) with high purity and yield.

Results: ^AlloMCAR-NKT cells exhibited potent cytotoxic activity against UEC tumor cells and CD1d⁺ tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Importantly, compared to conventional CAR-T cells, ^AlloMCAR-NKT cells demonstrated an improved safety profile, showing no evidence of graft-versus-host disease (GvHD) and minimal cytokine release syndrome (CRS)-related toxicity.

Conclusion: These findings highlight the potential of ^AlloMCAR-NKT cells as a safe and effective off-the-shelf cellular immunotherapy for the treatment of UEC and potentially other solid tumors characterized by an immunosuppressive microenvironment.

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.