Hepatocellular carcinoma (HCC) is a major liver malignancy and a leading cause of cancer-related mortality worldwide. Given its rising incidence and poor prognosis, there is an urgent need to elucidate the molecular mechanisms driving HCC progression and to develop novel targeted therapies. In this study, we identify MAML1 as a key contributor to HCC development. Elevated MAML1 expression strongly correlated with disease severity, whereas its knockdown suppressed HCC progression. Functionally, MAML1 promoted tumor malignancy by regulating STAT3 activity. Mechanistically, MAML1 interacted with STAT3 and enhanced its acetylation in a p300-dependent manner. Inhibition of STAT3 with a specific inhibitor attenuated MAML1-driven HCC progression. Furthermore, signaling pathway analyses revealed that YAP is the principal transcription factor regulating MAML1 expression by directly binding its promoter. Importantly, depletion of MAML1 diminished YAP-induced HCC malignancy and STAT3 activation, suggesting that YAP, MAML1, and STAT3 form a coordinated signaling axis that drives HCC progression. Collectively, these findings uncover a novel MAML1-centered signaling pathway in HCC and provide a compelling rationale for the development of MAML1-targeted clinical strategies for disease management.

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.

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.

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 A-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.

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.

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.

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.

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.

KMT2A-altered acute myeloid leukemia (AML) comprises rearrangements (KMT2A-r), partial tandem duplications (KMT2A-PTD), and dual alterations (KMT2A-r/PTD). In this study of 125 patients, these subgroups exhibited distinct molecular profiles: KMT2A-r cases were enriched in RAS pathway mutations, whereas KMT2A-PTD showed a higher burden of epigenetic alterations. Although overall survival (OS) and event-free survival (EFS) did not differ significantly between subgroups, prognosis was strongly influenced by fusion partners. MLLT3/ELL-rearranged cases showed superior outcomes, but concurrent KMT2A-PTD abrogated this survival advantage, AFDN and other fusions showed poor outcomes. We therefore propose a revised three-tier risk model integrating fusion partner and PTD status, which significantly stratified patient outcomes. The intermediate-risk group (MLLT3/ELL without PTD) had a 3-year OS of 78.1%, compared to 50.5% in the high-risk group (all PTD), and 34.9% in the very high-risk group (other KMT2A-r) (P = 0.044). For EFS, the rates were 71.0%, 40.1%, and 24.9%, respectively (P = 0.003). Allogeneic hematopoietic cell transplantation significantly improved survival, with 3-year OS rates of 75.2% in transplant recipients versus 22.5% in non-transplanted patients (P < 0.001), particularly in high-risk groups and when performed in first complete remission. These findings support the use of molecularly guided, risk-adapted therapy in KMT2A-altered AML.

MLL (KMT2A)-rearranged leukemia (MLL-r) is a highly aggressive hematologic malignancy driven by transcriptional dysregulation. Here, we identify EYA family phosphatase activity, particularly EYA1 and EYA3, as key vulnerabilities in MLL-r leukemia. The small molecule benzbromarone (BBR) selectively reduced viability in MLL-r and EYA-expressing MLL-nonrearranged (MLL-nr) leukemia cells. Inhibition of EYA PTP activity increased global RNA Pol II CTD Tyr1 phosphorylation, linking aberrant EYA PTP activity in responsive leukemia cells to transcriptional dysregulation. In vivo, BBR treatment significantly prolonged survival and reduced leukemia burden without overt toxicity. Furthermore, BBR synergized with the menin-MLL inhibitor VTP50469 and showed additive effects with the DOT1L inhibitor EPZ5676, the latter of which restored BBR sensitivity in previously BBR-unresponsive cells. These findings establish EYA PTP activity as a therapeutic target in MLL-r leukemia, support the use of EYA expression for identifying patients likely to benefit from BBR treatment, and highlight the potential of BBR-based combinations to improve response in this high-risk leukemia subtype.

Triple-negative breast cancer (TNBC) is notorious for its poor prognosis, high metastatic rates, and resistance to chemotherapy. We sought to investigate the anticancer effects of pitavastatin (PITA), a promising candidate for drug repurposing due to its potent inhibition of myeloid cell leukemia 1 (Mcl-1).

Chimeric antigen receptor T cell (CAR-T) is the main salvage therapy for relapsed or refractory large B-cell lymphoma (r/r LBCL). However, over 50% of patients relapse after CAR-T therapy. In this work, we transduced the CAR gene into hematopoietic stem cells (HSCs) using a lentiviral vector. Chimeric antigen receptor-modified HSC (CAR-HSCs) were transplanted into mice after lethal irradiation. CAR gene transduction did not compromise the ability of HSCs to expand, self-renew, or reconstitute. CAR was expressed on T cells, natural killer cells, B cells, monocytes, and neutrophils in the peripheral blood. CAR-HSCs transplantation significantly reduced CD19 tumor burden and prolonged the survival of mice with preclinical tumor without severe toxicity. CAR-HSCs also differentiated into different CAR-expressing immune cells that reshaped the tumor microenvironment by increasing the proportion of antitumor cells (like CD8 T cells) and the antitumor response, and by decreasing immunosuppressive cells, such as tumor-associated macrophage subtype 2. This study demonstrated a preclinical proof-of-principle for CAR-HSCs therapy in r/r LBCL, suggesting an opportunity for its clinical translation.

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.

Vaccination with tumor-(neo) antigen plus adjuvant is emerging as a promising cancer-therapy. However, as different adjuvants induce distinct immune cell and antibody (Ab) responses, selecting the right adjuvants remains challenging. Here, we evaluated the following vaccine adjuvants to promote protection against tumor-growth in mice and correlated IgG subclass and Fc N-glycosylation responses: Alum; the toll-like receptor activators Poly(I:C) and MPLA; Alum-Poly(I:C); and the more inflammatory water-in-oil adjuvants Montanide, IFA, CFA, and M.tb.-enriched (e)CFA. While Alum and Montanide failed to protect, MPLA and IFA tended to protect, and Poly(I:C), Alum-Poly(I:C), CFA, and eCFA significantly protected against tumor-growth. Across all adjuvants, tumor-protection correlated with the induction of highly activating IgG2(c/b) Abs and afucosylated (F0) IgG1 Abs, the latter showing up to 5% abundance. While all adjuvants transiently induced IgG1 F0 following initial immunization, Poly(I:C)- and eCFA-induced memory responses also generated IgG1 F0 after repeated antigen-exposure without adjuvants. Additionally, Poly(I:C)-induced tumor-protection was associated with high IgG2c/IgG1 ratios, high levels of IgG galactosylation and sialylation, and IFNγ-producing CD8 + Tc1-cells. Conversely, Ova-eCFA-induced tumor-protection was additionally associated with high levels of IgG across all subclasses, but low levels of galactosylation and sialylation, and CD8 + Tc17- and CD4 + Th17-cells. Accordingly, tumor protecting adjuvants may induce common but also different protecting programs. A tumor-antigen-specific IgG2a monoclonal (m)Ab protected against tumor-growth in both its de-galactosylated and galactosylated plus sialylated forms, suggesting common and possibly distinct protective mechanisms. Tumor-protection via serum transfer from Poly(I:C)-immunized mice depended more on NK-cells, whereas eCFA-induced and non-sialylated/non-galactosylated mAbs promoted neutrophil activation. These findings may help to improve tumor vaccination protocols.

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.

Approximately 30% of patients with stage T1 non-small cell lung cancer (NSCLC) have mediastinal (N2) lymph node metastasis; however, the underlying mechanism remains unclear.

Tumor-infiltrating lymphocyte (TIL) therapy, a highly promising form of adoptive cell therapy (ACT), has demonstrated success in treating advanced melanoma. Notably, innovative TIL-based monotherapies and combination regimens have provided durable clinical responses and survival benefits for patients with various solid tumors. This article summarizes recent advances in TIL therapy for solid tumors presented at the 2025 ASCO Annual Meeting, highlighting monotherapies such as Lifileucel, LM103, OBX-115, GT101, GT300, GT201, and HS-IT101, as well as combination strategies with the oncolytic adenovirus TILT-123 or pembrolizumab.

Brain metastases (BM) from non-small cell lung cancer (NSCLC) represent a significant clinical challenge, characterized by poor prognosis and treatment resistance. While cancer-associated fibroblasts (CAFs) are recognized as crucial components of the BM tumor microenvironment (TME), their mechanistic contributions to disease progression and therapeutic resistance remain poorly understood. In this study, we demonstrated that patient-derived BM-CAFs significantly enhanced NSCLC cell proliferation, migration, invasion and therapeutic resistance in vitro. Mechanistically, BM-CAFs promoted epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) phenotypes through upregulation of key transcription factors. In-vivo experiments showed that co-injection of NSCLC cells with BM-CAFs accelerated tumor growth and enhanced cisplatin resistance. Molecular analysis revealed these effects were mediated through distinct mechanisms whereby IL26 activated the JAK-STAT3 pathway, while CX3CL1 activated both JAK-STAT3 and AKT-mTOR pathways. Importantly, neutralizing antibodies against IL26 and CX3CL1 effectively suppressed their respective signaling pathways and reversed EMT and CSC characteristics. In summary, our findings establish the IL26 and CX3CL1 signaling as a critical mediator of BM-CAF-induced tumor progression and therapy resistance in NSCLC BM, suggesting a potential therapeutic strategy for this challenging disease.

Venous thromboembolism (VTE) remains a significant cause of morbidity and mortality, particularly among individuals with inherited thrombophilia. Despite the widespread use of thrombophilia testing, its clinical value is often questioned due to inconsistent guidelines and limited prospective evidence. Traditional testing panels target only a narrow set of common variants-such as Factor V Leiden and Prothrombin G20210A-and may miss rare, complex, or combined mutations, especially in high-risk patients, including pediatric populations and those with unprovoked events or atypical presentations. This correspondence aims to re-evaluate the clinical role of thrombophilia testing in light of next-generation sequencing (NGS), a technology that offers a broader, more precise assessment of heritable thrombotic risk. We discuss how NGS improves variant detection, enhances risk stratification, and supports a precision medicine framework-particularly in clinical scenarios where standard algorithms fail. By integrating emerging evidence and real-world applications, we advocate for an updated, individualized approach to genetic testing in VTE care.

Zevorcabtagene autoleucel (zevor-cel) is a fully human autologous CAR T-cell therapy targeting B-cell maturation antigen approved in China since 2024 for patients with relapsed/refractory multiple myeloma (RRMM).