Telomerase is active in the majority of high-risk neuroblastomas, a pediatric tumor associated with poor patient outcomes. In other cancer types, resistance to immune checkpoint blockade was overcome by induction of telomere dysfunction using the telomerase substrate precursor 6-thio-2'-deoxyguanosine (6-thio-dG). Here, we explored whether induction of telomere dysfunction improves the anti-tumor efficacy of immune checkpoint inhibition in neuroblastoma. 6-thio-dG treatment induced the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and programmed cell death ligand-1 (PD-L1) expression in murine neuroblastoma cells in vitro. In a MYCN;ALKF1174L-driven transgenic neuroblastoma mouse model, 6-thio-dG treatment delayed tumor growth and prolonged survival. Treatment with anti-PD-L1 also led to growth delay and improved survival, which occurred; however, only after an initial lag phase. Combination with anti-PD-L1 improved the anti-tumor effects of 6-thio-dG and overcame the initial lag phase of anti-PD-L1 treatment. Mechanistically, 6-thio-dG combined with anti-PD-L1 treatment induced cGAS and PD-L1 expression and promoted immune cell infiltration in the tumors. Our findings suggest that 6-thio-dG treatment activates the cGAS-STING pathway in neuroblastoma and that induction of telomere dysfunction in combination with immune checkpoint blockade boosts intratumoral immune cell infiltration and improves survival in a high-risk neuroblastoma mouse model.

Cancer therapy imposes sustained mechanical and biochemical stress on lymphatic tissues, reshaping the signaling environments in which endothelial and contractile programs operate via molecular signals, cell-cell interactions, and mechanical forces. We propose that cancer-associated lymphedema arises from destabilized receptor crosstalk within integrated lymphatic signaling units rather than solely from anatomical insufficiency. Lymphatic vessels function as multicellular signal-processing systems in which receptor activity is context dependent and continuously modulated by ligand availability, tissue stiffness, inflammatory tone, and metabolic state. Under therapeutic stress, receptor systems that are secondary under homeostatic conditions, including mechanosensitive ion channels, purinergic receptors, and stress-responsive G protein-coupled receptors, can exert disproportionate influence over endothelial transcription, barrier function, contractile coordination, and immune-vascular feedback loops. Sustained activation of these networks may reinforce inflammatory and remodeling programs, providing a mechanistic explanation for delayed onset, nonlinear progression, and interindividual variability. This signaling-centered framework positions lymphatic failure after cancer therapy as a disorder of network integration and identifies stress-responsive receptor systems as tractable points for early intervention.

Supernumerary centrosomes are a hallmark of cancer. To maintain viability, cancer cells cluster these centrosomes during mitosis, enabling bipolar division similar to that of normal cells. Disruption of this centrosome clustering leads to multipolar anaphase and apoptosis (anaphase catastrophe), which selectively eliminates cancer cells harboring supernumerary centrosomes. In this context, because the motor protein KIFC1 contributes to centrosome clustering, we investigated whether targeting of this mechanism through KIFC1 inhibition could be exploited in small-cell lung cancer (SCLC), an aggressive malignancy with limited treatment options and poor prognosis. Through in silico and in vitro analyses, as well as IHC of clinical samples, we found that KIFC1 is overexpressed and that centrosome amplification occurs more frequently in SCLC compared with normal tissues and other cancer types. Pharmacological and genetic inhibition of KIFC1 disrupted the clustering of supernumerary centrosomes, triggered multipolar mitosis, and exerted antineoplastic effects in SCLC cells, with minimal effects on noncancerous cells. These findings were validated and extended in vivo using SCLC xenograft models. Finally, cotargeting KIFC1 and the centrosome duplication regulator PLK4 further enhanced growth suppression in SCLC cells. Together, these results suggest that disrupting centrosome clustering and triggering anaphase catastrophe via KIFC1 inhibition may represent a promising therapeutic strategy for SCLC.

Cancer is a leading cause of mortality worldwide, yet access to specialized pathology services remains limited in many low- and middle-income countries, including Tanzania. Telepathology offers a practical means to expand diagnostic capacity and improve timely cancer care. Through a partnership with the American Society for Clinical Pathology (ASCP) and Duke University, Kilimanjaro Christian Medical Centre (KCMC) implemented a telepathology consultation platform to provide expert review for diagnostically challenging cases.

The bone marrow workshop (session 3), held at the 22nd Meeting of the European Association for Hematopathology/Society of Hematopathology in Dubrovnik, was dedicated to myeloid/lymphoid precursor cell neoplasms and mixed-phenotype acute leukemias (MPALs). We hereby report the clinicopathologic, immunophenotypic, and genetic features of the submitted cases.

Neuropilin-1 (NRP1) is overexpressed in various malignant solid tumors, modulating the tumor microenvironment (TME) via multiple mechanisms to promote immune suppression, angiogenesis, and epithelial-mesenchymal transition (EMT), ultimately resulting in poor patient survival. Autophagy, a highly conserved cellular self-degradation process, plays a stage-dependent, bidirectional role in cancer. At early stages it suppresses tumorigenesis by clearing damaged cellular components, whereas at advanced stages it supports tumor survival under stress and thereby enhances proliferation, invasiveness, and therapy resistance. The interplay between NRP1 and autophagy in the TME is characterized by reciprocal regulation: NRP1 activates certain pathways to regulate autophagy, whereas autophagy induction promotes NRP1 degradation. This bidirectional interplay directly governs tumor progression and therapy resistance. Although prior studies have provided some clues about their interaction, the regulatory network and the precise mechanisms linking NRP1 and autophagy in the TME remain incompletely characterized. Precision therapies targeting the NRP1-autophagy axis still face multiple obstacles. This review synthesizes data from the atlas cancer genome (TCGA), the genotype-tissue expression (GTEx) database, and the human autophagy database (HADb) to explore associations between NRP1 and autophagy-related gene (ATG) in expression and prognosis, elucidate NRP1-autophagy interaction mechanisms and therapeutic opportunities and challenges in targeting the NRP1-autophagy axis. Pan-cancer analysis showed significant upregulation of NRP1 in 10 solid tumor types and revealed co-expression relationships between NRP1 and 340 ATGs. Among these, co-expression patterns involving genes such as CXCR4 and HSPA5 had significant prognostic value in gastric cancer and glioblastoma. This review systematically explores the panoramic regulatory framework of the NRP1-autophagy axis in the tumor immune microenvironment through bidirectional regulation of activating immunity and inhibitory immunity at the pan-cancer level. It fills the gap in the systematic summary of the NRP1-autophagy axis in regulating the dynamics of the tumor immune microenvironment, and provides a theoretical basis for the clinical translation of combination chemotherapy and immunotherapy targeting the NRP1-autophagy axis.

Exosomes can promote tumor development and regulate tumor immune responses, making them of significant value in Lung Adenocarcinoma (LUAD) management. In-depth exploration of exosome-related genes in LUAD is of great significance for expanding LUAD clinical treatment options.

Therapeutic resistance remains the principal cause of mortality in breast cancer. While the tumor microenvironment (TME) is a key contributor, therapies targeting isolated TME components, whether immune, metabolic, or spatial, have largely failed due to compensatory adaptations and ecological resilience. This review synthesizes recent advances to propose a tripartite "Immune-Metabolic-Spatial" axis as the fundamental organizer of a robust resistance niche. We elucidate how immunosuppressive cells, such as TAMs and Tregs, are metabolically sustained by altered nutrient availability like lactate and hypoxia, while spatial constraints, including CAF-deposited ECM and DDR1-mediated collagen alignment, physically impede drug delivery and immune infiltration. Critically, we highlight reciprocal crosstalk where metabolic reprogramming dictates immune cell function, in turn influencing stromal remodeling to create a self-reinforcing resistance loop. Beyond mechanism, we evaluate emerging strategies that concurrently target multiple axes, such as combining immune checkpoint blockade with metabolic inhibitors or stromal disruptors. Finally, we discuss clinical translation through biomarker development and innovative trial designs, framing the tripartite axis as an actionable framework for overcoming therapeutic resistance.

Bladder cancer is the tenth most common cancer worldwide and the sixth most common among men. However, research into representative tumor models for bladder cancer remains underdeveloped, limiting insights into tumor biology and drug development.

Unintentional weight loss (UWL) is the primary diagnostic parameter for cancer cachexia in the clinic. Prompt identification of UWL can lead to earlier diagnoses and interventions for cancer. This study investigates the frequency and timing of UWL documentation and diagnoses in a cohort of cancer patients with measured UWL and sought to understand how recognition of UWL is related to stage of disease at cancer diagnosis.

Epithelioid angiosarcoma (EA) is a malignant tumor of endothelium origin that most commonly arises in the deep soft tissues of extremities but may occasionally be primary in skin, adrenal gland, and bone. A 72-year-old male presented with a painless enlargement of his thyroid for more than 10 days before hospitalization. A walnut-sized mass in the right thyroid was found simultaneously by palpation and Color Doppler Ultrasound. After a total thyroidectomy was performed, a mass with a size of 4.5 cm × 3.5 cm was found at the lower pole of the right thyroid gland. Histologically, the tumor was diffusely distributed in a sheet-like pattern, with tumor cells being epithelioid. There was extensive coagulative necrosis while no components of papillary carcinoma, follicular carcinoma and insular poorly differentiated carcinoma were noticed. CD31 and vimentin were positive for immunostaining. The diagnosis of primary epithelioid angiosarcoma of right thyroid was then given to the patient. Eleven months after the operation, the patient died from brain metastasis. It is suggested that primary epithelioid angiosarcoma of thyroid, as an extremely rare tumor, have no characteristic clinical manifestations, laboratory and imaging examinations, and the diagnosis mainly depend on its unique clinical pathological features. Although extensive surgical resection is the preferred treatment, the prognosis is still very poor.

Combined large cell neuroendocrine carcinoma (LCNEC) of the endometrium is rare and carries a poor prognosis. A 61-year-old woman with suspected endometrial serous carcinoma was referred to our hospital. Imaging studies staged the disease as stage IIIC1. We performed a total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and retroperitoneal lymph node dissection. Histopathological examination revealed a combination of LCNEC, endometrioid carcinoma, and multiple lymph node metastases. Postoperative computed tomography showed multiple pulmonary metastases not detected preoperatively. Given the advanced and recurrent nature of the disease, treatment with paclitaxel, carboplatin, and durvalumab was initiated. After the first cycle, the pulmonary metastases disappeared. Maintenance therapy with durvalumab and olaparib was continued because of proficient mismatch repair status. This case demonstrates that durvalumab may be a viable treatment option for endometrial LCNEC, as it is also approved for small cell lung cancer, which shares similarities with neuroendocrine carcinoma.

Angiogenesis, which is the formation of new blood vessels from existing vasculature, exhibits a pivotal role in breast cancer progression and promotes metastasis. This complex biological process is influenced by the dynamic balance of pro- and anti-angiogenic factors within the tumor microenvironment, such as vascular endothelial growth factor, fibroblast growth factors, and angiopoietins. Targeted therapeutic strategies have been developed to interfere with angiogenic signaling, aiming to normalize or inhibit the tumor vasculature. In recent years, miRNAs have arisen as crucial post-transcriptional regulators of gene expression implicated in angiogenic homeostasis. These microRNAs can function as either promoters or suppressors of angiogenesis by targeting mRNAs that encode angiogenic factors or other signaling molecules. Deregulated expressions of these miRNAs in BC are associated with perturbed angiogenesis, tumor progression, and therapeutic resistance. This review presents a thorough overview of the molecular processes controlling angiogenesis in BC and highlights the emerging roles of angioregulatory miRNAs. The article also discusses the therapeutic potential of targeting miRNAs to modulate tumor angiogenesis, providing novel insights for the development of miRNA-based diagnostics and therapeutics in BC management.

Despite the emerging role of the gut microbiome in colorectal cancer (CRC), its significance in early-onset CRC (EOCRC, < 50 y) versus late-onset CRC (LOCRC) and the molecular differences between proximal and distal CRC remain poorly understood. To circumvent the logistical and patient compliance challenges of stool collection, we explored the utility of anal swabs as a convenient alternative for characterizing gut microbiome signatures in CRC. We profiled the CRC microbiome using anal swabs (n = 76) and stool samples (n = 33) by 16S rRNA sequencing. Diversity indices were compared using Wilcoxon tests, compositional differences assessed by PERMANOVA, and correlations were performed in paired samples. Correlation analysis revealed strong associations between microbial phyla (Bacteroidetes, R = 0.86, p = 4.7 × 10⁻⁶; Firmicutes, R = 0.65, p = 3.4 × 10⁻³; Verrucomicrobiota, R = 0.81, p = 4.8 × 10⁻⁵; and Fusobacterium, R = 0.80, p = 7.3 × 10⁻⁵) and major genera (Bacteroides, R = 0.88, p = 1.7 × 10⁻⁵; Fusobacetrium, R = 0.75, p = 1.5 × 10⁻³; Blautia, R = 0.77, p = 8.5 × 10⁻⁴; and Bifidobacterium, R = 0.81, p = 3.3 × 10⁻⁴) across sample types, validating the use of anal swabs. However, Actinobacteriota and Prevotella were not correlated, likely reflecting the perianal skin-associated microbiota and underscoring the need for validation against stool or mucosal biopsies. Importantly, anal swabs revealed associations between Negativicoccus and proximal CRC (p = 0.047) and between the Fusobacteriota phylum and LOCRC (p = 0.042), suggesting subtype-specific CRC subtypes. In mechanistic studies, using the mucous-secreting HT-29 MTX cell line, we observed that Negativicoccus was associated with activation the RAS/MAPK pathway, upregulated c-MYC, KRAS, MAPK1, and Cyclin D1 (p < 0.05) and increased proinflammatory cytokines (IL-8) (p < 0.05), thereby increasing cell proliferation. In contrast, Fusobacterium modulates the WNT/β-catenin pathway, increasing β-catenin and AXIN1 (p < 0.05), promoting cell migration (p < 0.05), and extracellular matrix (ECM) remodeling. These findings highlight distinct microbial contributions to CRC pathogenesis, with Negativicoccus influencing proliferation and inflammation, whereas Fusobacterium promotes migration and invasion. Understanding these pathways offers potential for harnessing the gut microbiome's diagnostic and therapeutic power in CRC.

Terminalia macroptera (Combretaceae) is an important medicinal plant in the traditional pharmacopeia in most tropical areas, where its different parts are used in treating illnesses including cancer.

SWI/SNF chromatin remodeling complexes are perturbed in 20% of all cancers and in several developmental disorders, yet the mechanisms by which these mutations dysregulate transcription and drive disease are poorly understood. To both elucidate these mechanisms and identify vulnerabilities caused by these mutations, we leverage genome-wide CRISPR-Cas9 screening in hundreds of cancer cell lines and identify the chromatin reader protein PHIP as a specific dependency in cancers with broadly disrupted SWI/SNF function. Mechanistically, we reveal that PHIP cooperates with SWI/SNF to facilitate transcriptional activation by ubiquitinating and suppressing subunits of the repressive Nucleosome Remodeling and Deacetylase (NuRD) complex. We demonstrate that loss of SWI/SNF results in NuRD complexes accumulating at promoters where they would otherwise cause widespread transcriptional silencing if not antagonized by PHIP. Collectively, we identify PHIP as a regulator of the interplay between distinct chromatin regulators that function in development and disease and as a targetable vulnerability in cancers with broad SWI/SNF inactivation.

Chemotherapy resistance remains a critical bottleneck limiting its clinical efficacy in small cell lung cancer (SCLC), with its core mechanisms and targeted intervention strategies urgently requiring breakthroughs. Our study revealed that the BMX (bone marrow tyrosine kinase on chromosome X)-E2F1 (E2F transcription factor 1) axis is a pivotal regulator of chemoresistance in SCLC. Synchronous upregulation of phosphorylated BMX (Tyr566) and E2F1 was observed in SCLC tissues and cells. Mechanistically, BMX stabilized E2F1 via the ERK1/2 (extracellular signal-regulated kinase 1/2)-Cyclin D1/CDK4/6 (cyclin-dependent kinase 4/6) signaling axis, phosphorylating E2F1 at Ser332/337 and inhibiting its degradation via the ubiquitin-proteasome pathway. Inhibition or knockdown of BMX reduced E2F1 stability, promoting its degradation and reversing chemoresistance. E2F1 knockdown decreased the expression of genes associated with cell cycle regulation, migration, invasion, and DNA repair, further sensitizing chemoresistant SCLC cells to cisplatin. We also discovered IHMT-15137, a potent and selective BMX inhibitor. In vitro studies using SCLC patient-derived cells (PDCs)/patient-derived organoids (PDOs) and chemoresistant cell lines revealed that IHMT-15137, combined with cisplatin, synergistically induced cell cycle arrest, apoptosis, and DNA damage while suppressing cell migration and invasion. In vivo xenograft models demonstrated that the combination significantly inhibited tumor growth without causing significant toxicity. Our findings reveal the molecular mechanisms of SCLC chemoresistance and suggest potential therapeutic strategies targeting the BMX-E2F1 axis to overcome this challenge.

Resistance to lenvatinib remains a major barrier in the treatment of advanced hepatocellular carcinoma (HCC), underscoring the urgent need to elucidate the underlying mechanisms and identify actionable therapeutic targets. In this study, we identified a neurosecretory factor derived from HCC cells, Nerve Growth Factor (NGF), as a critical mediator of lenvatinib resistance. Utilizing an innovative in vivo-in vitro cross-circulated strategy, we established a phenotypically stable lenvatinib-resistant HCC cell line (LenR-cells). Through proteomic screening of conditioned media and subsequent functional validation, we demonstrated that NGF secretion progressively increases with the acquisition of resistance. Mechanistically, we uncovered that the SRPK1-SRSF1 axis drives enhanced NGF production by regulating alternative splicing of its precursor transcript, specifically promoting the expression of a shorter, translationally efficient isoform (proNGF-B). Elevated NGF subsequently activates the non-canonical MAPK pathway (MEK5-ERK5) via its high-affinity receptor TrkA, thereby sustaining tumor cell viability and proliferation under sustained tyrosine kinase inhibitor pressure. Critically, pharmacological co-targeting of TrkA with the clinically approved inhibitor larotrectinib restored lenvatinib sensitivity in both patient-derived organoids and xenograft models, producing marked synergistic anti-tumor effects without evidence of exacerbated toxicity. Clinical analyses of two independent patient cohorts further confirmed that elevated NGF expression is significantly associated with poor response to lenvatinib, shorter recurrence-free survival, and worse overall survival. Our findings unveil a critical and previously underappreciated role for tumor-derived NGF in orchestrating adaptive signaling through a precise post-transcriptional regulatory circuit and propose a readily translatable, biomarker-guided combination strategy to overcome lenvatinib resistance in HCC.

In this phase 3 trial, penpulimab combined with chemotherapy was assessed against a regimen of placebo plus chemotherapy for the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma (R/M NPC). 291 patients were randomised and allocated in a 1:1 ratio in order to receive penpulimab (n = 144; 200 mg) or placebo (n = 147; 200 mg), plus chemotherapy (cisplatin/carboplatin and gemcitabine) every 3 weeks. Patients followed by maintenance therapy with penpulimab or placebo after 6 cycles. The primary endpoint of this study was progression-free survival (PFS) according to RECIST v1.1, and a significantly longer median PFS in the penpulimab arm versus the placebo arm (9.63 versus 7.00 months; hazard ratio 0.45, 95% CI: 0.33-0.62, P < 0.0001) was demonstrated in this prespecified interim analysis. The key secondary endpoint was the overall survival (OS). However, the OS data were still immature, and the median OS was not achieved (hazard ratio, 0.94; 95% CI: 0.63-1.40). The occurrence of treatment-related adverse events (grade ≥ 3) was 89.0% and 85.9% in two arms, with the most common being reduced the quantity of neutrophil (56.2% vs. 62.0%), reduced the quantity of white blood cell (54.1% vs. 54.9%), and anemia (45.2% vs. 38.7%). In the penpulimab arm, 6 patients (4.1%) experienced immune-related adverse events (grade ≥ 3). Adding penpulimab to chemotherapy led to a notable enhancement in PFS for the first-line R/M NPC treatment, alongside a safety profile that was both manageable and tolerable. ClinicalTrials.gov identifier NCT04974398.

Perineural invasion (PNI), a prominent pathological feature of pancreatic ductal adenocarcinoma (PDAC), is closely associated with poor prognosis. Clarifying its mechanism is therefore critical for developing new therapies. Recent research has focused on the crosstalk between tumors and Schwann cells (SCs), particularly the role of SC dedifferentiation in facilitating PNI. In this study, by integrating RNA-seq, spatial transcriptomics, and single-cell analysis of clinical samples, we identified significant enrichment of dedifferentiated SCs and upregulation of key markers (p75NTR, SOX2, and c-Jun) in PNI regions. Moreover, PTGES was more highly expressed in the central region of the PNI than in the other regions of the PNI. Coculture experiments revealed that PANC-1 and BxPC-3 cells enhanced SC dedifferentiation, and this process facilitated pancreatic cancer cell malignancy. Furthermore, PTGES upregulation in the coculture system mediated prostaglandin E2 (PGE2) synthesis. Functional experiments revealed that PGE₂ drove morphological alterations in SCs-characterized by bipolar stretching-and elevated the expression of dedifferentiation markers, including p75NTR, c-Jun, SOX2, and GDNF. In the 3D coculture model, treatment with a PTGES inhibitor (CAY10526), siPTGES or PTGES-KO impaired the directional migration and neurite outgrowth of SCs toward PDAC cells. Mechanistically, PGE₂-stimulated SCs secrete elevated levels of LIF and ADAMTS-1, factors that promote extracellular matrix degradation and neural remodeling to facilitate tumor invasion. In summary, we delineate a novel paracrine axis in which PDAC-derived PGE₂ drives SC dedifferentiation and the production of proinvasive factors (LIF and ADAMTS-1), collectively establishing a microenvironment conducive to PNI. Our findings suggest that the PTGES-SC axis is a promising therapeutic target for inhibiting PNI in PDAC.