Cantharidin (CTD) is a natural anticancer compound whose clinical application is limited by poor water solubility, low bioavailability, and significant toxicity. To develop a more effective and safer therapeutic strategy, we proposed a synergistic combination therapy by integrating CTD with staurosporine (STS), a protein kinase inhibitor that shares complementary mechanisms of action targeting the mTOR/HIF-1α/VEGF pathway. We further developed an aptamer-guided liposomal nanosystem for the co-delivery of CTD and STS (Apt/CTD-STS/NL), aiming to enhance tumor targeting, improve bioavailability, and reduce the systemic toxicity of both drugs.

Muscle-invasive bladder cancer (MIBC) is an aggressive disease that typically requires multimodal treatment. Recently, immunotherapy strategies targeting the tumor microenvironment (TME) have reshaped the therapeutic approach for MIBC. Our study explores the expression of immune checkpoint biomarkers TIGIT, LAG-3, and PD-L1 across molecular subtypes of MIBC.

'Cutaneous T-cell lymphoma (CTCL), particularly tumor stage mycosis fungoides (MF), presents significant therapeutic challenges due to limited treatment efficacy. This study addresses the unmet need for novel targeted therapies targeting the constitutively hyperactive STAT3/5 pathway.

Diffuse Midline Glioma (DMG), often formerly called Diffuse Intrinsic Pontine Glioma (DIPG) when in the brainstem, DMG/DIPG is a lethal pediatric brain tumor defined by infiltrative growth, resistance to conventional therapies, and a profound immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), including resident microglia and infiltrating monocyte-derived macrophages, are the predominant immune population in DMG/DIPG. These cells adopt an immunosuppressive, pro-tumor state, promoting immune evasion and limiting the efficacy of therapies such as chimeric antigen receptor (CAR) T cells. Reprogramming TAMs toward a pro-inflammatory, anti-tumor phenotype offers a promising strategy to remodel the DMG/DIPG microenvironment. This review is the first to provide a comprehensive, integrative perspective on TAM-directed strategies in DMG/DIPG, spanning molecular, epigenetic, and biophysical approaches. We summarize TAM-mediated tumor progression and therapy resistance, and discuss molecular reprogramming strategies, including colony-stimulating factor 1 receptor (CSF1R) inhibition, microRNA-based circuits, and epigenetic modulators such as histone deacetylase (HDAC) and bromodomain and extra-terminal domain (BET) inhibitors. Nanoparticle-mediated delivery systems allow selective TAM targeting and enhanced blood-brain barrier (BBB) penetration. Additional strategies, including oncolytic viruses and macrophage-specific checkpoint blockade (e.g., CD47/SIRPα axis inhibitors), simultaneously promote tumor clearance and immune activation. We also highlight emerging biophysical approaches to modulate TAM function in situ. Photodynamic therapy (PDT) induces immunogenic cell death and pro-inflammatory macrophage activity, while focused ultrasound (FUS) transiently disrupts the BBB to enhance drug delivery and immune infiltration. Photobiomodulation and low-level light therapy (LLLT) may influence macrophage metabolism and phenotype, though their application in DMG/DIPG remains largely unexplored. Finally, we discuss combinatorial strategies integrating TAM reprogramming with CAR T cell therapy or chemotherapy to overcome the immunologically "cold" nature of DMG/DIPG. By uniting mechanistic insights with translational opportunities, this review establishes TAM reprogramming as a critical, underexplored frontier in DMG/DIPG immunotherapy, offering the potential to render an otherwise intractable tumor immunologically targetable.

Hsa-miR-99a has been linked to the advancement of several malignancies, including colorectal cancer (CRC). This investigation seeks to elucidate its function and regulatory network in CRC.

Undifferentiated small round cell sarcoma (USRCS) are a rare, aggressive group of tumors associated with rapid progression, metastasis, and poor prognosis. Preoperative diagnosis remains elusive, particularly for extraosseous variants, and effective treatments are lacking. This case reports the use of pembrolizumab, bevacizumab, and conventional chemotherapy (gemcitabine plus paclitaxel) as a first-line treatment for a patient with primary USRCS in the gallbladder neck; the patient achieved remarkable partial remission for more than 9 months. This case represents the second documented instance of gallbladder USRCS and the first managed with this specific combination regimen. These findings suggest that integrating immunotherapy and targeted agents with conventional chemotherapy may offer a promising therapeutic strategy for USRCS.

This study aimed to evaluate the diagnostic yield and complications associated with computed tomography (CT)-guided transthoracic core-needle biopsy (CNB) of lung lesions and to identify factors influencing biopsy outcomes.

Gastric carcinoma poses a significant global health challenge, often diagnosed late due to its similarity to chronic gastric conditions. Helicobacter pylori (Hp) infection plays a crucial role in gastric carcinogenesis through inflammation and the release of virulent products.

Ovarian cancer remains the most lethal gynecologic cancer and has the worst prognosis among all female reproductive malignancies worldwide. In Ethiopia, ovarian cancer is the third most prevalent malignancy among women, following breast and cervical cancers. Despite extensive research on the topic, evidence regarding the determinants of mortality among ovarian cancer patients remains limited. Therefore, the primary aim of this study was to identify predictors of ovarian cancer mortality among patients receiving care at oncology centers in Addis Ababa, Ethiopia.

Pulmonary metastasectomy is an established part of the multimodal treatment of various malignant diseases. While the procedure typically focuses on complete removal of metastatic lesions, the role of mediastinal lymph node involvement remains unclear. We aimed to analyze the prevalence of lymph node involvement and its impact on prognosis in patients undergoing pulmonary metastasectomy.

T cell dysfunction (TCD) plays a critical role in cancer progression and significantly impacts patient outcomes. Despite its importance, the exact molecular mechanisms underlying TCD remain poorly understood. To address this, we constructed a comprehensive pan-cancer landscape of TCD, with a particular focus on identifying miRNA biomarkers that define and predict TCD severity. Our analysis revealed six key miRNAs (miR-203b, miR-214, miR-4772, miR-141, miR-200a, and miR-200b) that were closely associated with varying degrees of TCD. These prognostic miRNAs not only exhibited distinct expression patterns across four identified TCD subtypes (from low to high TCD severity) but also demonstrated strong predictive performance in classifying patients with different levels of TCD. The identified miRNA signatures serve as reliable biomarkers for stratifying patients into high-risk and low-risk groups, with higher TCD levels correlating to poorer overall survival. In addition to miRNA biomarkers, we observed that patients with severe TCD exhibited increased infiltration of immune cells and macrophages and dysregulation of DNA methylation patterns. Patients with higher degrees of TCD displayed low methylation levels, which further contributed to the progression of T cell dysfunction. In summary, our study highlights the pivotal role of miRNA biomarkers in shaping the landscape of T cell dysfunction across cancers. These miRNAs serve as both prognostic indicators and predictive tools, enabling accurate classification of TCD severity and offering new avenues for therapeutic exploration and patient stratification in cancer immunotherapy.

Breast cancer treatment depends on tumour subtypes. In particular, patients with oestrogen receptor-positive (ER+) tumours are treated with hormonal therapy. In Sweden, the recommended treatment duration is five years, with current guidelines advising an additional five years for women at high risk of disease recurrence. However, the impact of extended therapy on metastatic progression has not been thoroughly quantified at the population level. In this article, we use a modelling approach to estimate the time-varying effect of hormonal treatment on time to metastasis. The model is then used to compare 5- and 10-year treatment durations at different tumour sizes. Rather than using a common statistical modelling approach, we incorporate the effect of endocrine therapy within a biologically inspired natural history model of breast cancer to accommodate key features of the expected treatment-outcome relationship. We fitted the model using maximum likelihood and data from a cohort of 9,716 incident cases diagnosed with invasive ER+ breast cancer between 2005 and 2020. Based on our main model estimates, the 10-year metastasis-free survival would improve from 92.8% to 96.1% for a symptomatic patient with a 20 mm tumour with ten years (instead of five) of hormonal treatment. Our natural history model quantifies the impact of prolonged hormonal treatment on metastatic events in ER+ breast cancer patients, including features that are not captured by traditional statistical approaches. Results suggest a significant reduction in metastatic tumour growth rates during treatment, supporting the extension of endocrine therapy to 10 years for people with large tumours.

Although some patients with cervical cancer respond well to therapy, others show minimal response and develop recurrence after treatment. A better understanding of the molecular features that distinguish and drive the variable responses to therapy is needed to improve patient stratification and treatment. In this issue of Cancer Research, Sandoval and colleagues conduct integrated multiomic analyses of longitudinal patient cohorts to characterize the molecular and cellular reprogramming induced by chemoradiation therapy (CRT). The analyses show that treatment fundamentally reshapes the tumor microenvironment, inducing a shift from lymphoid-dominant to myeloid-dominant immune infiltration. The authors also identify the induction of MDM2-dependent DNA damage response specifically in tumor cells. Leveraging both treatment-naïve and CRT-exposed patient-derived xenografts, they demonstrate that MDM2 inhibition enhances radiation response, with the greatest efficacy in therapy-resistant tumors. These findings identify MDM2 as a rational, therapy-induced target emerging from unbiased analysis. As the field moves toward integrating targeted therapies and immunotherapy with standard chemoradiation, this study underscores the importance of understanding when, where, and in whom to intervene. See related article by Sandoval et al., p. 1639.

Serous tubal intraepithelial carcinomas (STIC) are precursors of high-grade serous carcinoma (HGSC), the deadliest subtype of ovarian carcinoma. To establish clinically actionable strategies against these lesions, a better understanding of the mutational, transcriptional, and genetic/epigenetic alterations, as well as interactions among epithelial, immune, and stromal cells, is essential. In this issue of Cancer Research, Shih and colleagues conducted the first integrated spatial multiomics analysis of ovarian precancerous lesions, revealing substantial heterogeneity within the fallopian tube epithelium that may influence cancer susceptibility. They described four molecular subclasses of STICs according to their epithelial transcriptomic profiles: proliferative, immunoreactive, mixed, and dormant (PIMD) subtypes. Molecular links of this "PIMD" STIC subclassification to tumor progression were proposed, uncovering early events in ovarian tumorigenesis and potential genetic drivers of STIC heterogeneity. Furthermore, the STIC subtypes showed distinct histologic and molecular characteristics that warrant further investigation to develop a deeper understanding of the molecular and cellular processes driving the evolution of STIC heterogeneity, which may facilitate the development of early diagnostic approaches for HGSC. Collectively, the findings that not all STICs are equal open new avenues for further clinicopathologic, translational, and basic research to improve risk classification and early intervention in HGSC. See related article by Chang et al., p. 1739.

Tensins are a family of adhesion proteins that play a role in constructing the cytoskeleton, as well as in intracellular and extracellular communication. Their expression was evaluated in 22 pancreatic cancer patients using the immunohistochemistry method. TNS1 expression occurred more frequently among patients with tumor diameter ≥ 2 cm, which may suggest an association with the development of pancreatic cancer. Intraductal TNS1 was observed less often with presence of necrosis and hemorrhages in tumor. The fact that cancer cells secrete TNS1 suggests that it could be investigated as a potential target for liquid biopsies. TNS4 expression occurred more frequently among females and was observed when necrosis in tumor was strong. TNS2 and TNS3 are not involved in the development of ductal pancreatic adenocarcinoma.

Early-stage diffuse large B-cell lymphoma (ESDLBCL) in older adults is understudied, and existing prognostic tools such as the stage-adjusted International Prognostic Index (Sa-IPI) may not adequately account for comorbidity and age-related vulnerability. This study evaluated long-term outcomes and developed a simplified prognostic index for patients aged ≥ 60 years with ESDLBCL.

ObjectiveTo assess the overall survival (OS) and cancer-specific survival (CSS) in patients with different primary locations of hypopharyngeal squamous cell carcinoma (HSCC) and to develop a predictive model incorporating key clinical and treatment variables (including systemic therapy) to serve as a prognostic reference for patients with locally advanced HSCC.MethodsThis retrospective cohort study extracted data for 1,591 patients with locally advanced HSCC from the Surveillance, Epidemiology, and End Results (SEER) database. X-tile software was used to determine optimal cutoff values for continuous variables. Kaplan-Meier analysis compared survival by primary site. Independent risk factors were identified using stepwise Cox regression, and a nomogram was constructed. Model performance was assessed using the concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis (DCA).ResultsOS and CSS differed significantly by primary site. Stepwise Cox analysis identified 13 independent prognostic factors. The nomogram showed a C-index of 0.727 in both training and validation sets. The AUCs for 1-, 3-, and 5-year OS were 0.792, 0.791, 0.788 (training) and 0.780, 0.796, 0.789 (validation). Calibration curves indicated good agreement between predicted and observed outcomes. DCA demonstrated superior net benefit over TNM staging alone.ConclusionPrognosis in locally advanced HSCC varies by primary site. The developed nomogram provides moderate prognostic accuracy and may serve as a supplementary tool for risk stratification and clinical discussion, though external validation is warranted.

Tenosynovial giant cell tumors (TGCTs), a rare benign mesenchymal neoplasm of synovial tissue, often incurs chronic pain, joint destruction and repeated surgery, markedly impairing quality of life. Historically, surgery was the only effective option. The colony-stimulating factor 1 receptor (CSF1R) inhibitor pexidartinib broke this therapeutic deadlock, pioneering systemic therapy and shaping subsequent drug development. Further exploration of pexidartinib and associated clinical studies in the field of TGCT have continued following its approval, with updated data and outcomes continuing to play a crucial role in guiding the clinical application of pexidartinib for treatment of TGCT. This review provides a comprehensive summary of the preclinical and clinical development of pexidartinib for treatment of TGCT, and highlights the recent updates in clinical studies and findings since its approval. These include long-term efficacy, optimization of therapeutic strategies, management of risks associated with long-term use, and real-world patient-reported outcomes, all of importance and value for patients and physicians in clinical practice. Here we aim to provide guidance for the improved clinical application of this drug class to enhance patient benefits in TGCT treatment.

Bladder cancer is a common urogenital malignancy that remains difficult to treat, particularly due to therapeutic resistance, such as resistance to cisplatin, in which cancer stem cells (CSCs) play a central role. This study investigates the combination of 5-aminolevulinic acid-mediated photodynamic therapy (5-ALA-PDT) and berbamine as a potential multimodal treatment strategy using the bladder cancer cell lines RT112 and J82, their cisplatin-resistant variants, and generated CSC-like cells. Berbamine is a natural plant compound and was confirmed in this study to have anticancer properties by inhibiting cell migration and invasion, and by inducing apoptosis. This study also showed that berbamine enhances the accumulation of protoporphyrin IX (PpIX), the photosensitizer induced by 5-ALA. 5-ALA-PDT destroys cancer cells by stimulating PpIX via 635 nm red laser light to produce reactive oxygen species (ROS). This was found to happen in all tested cell lines, whereas berbamine could modulate the cell destruction in a concentration-dependent manner and was influenced by the specific biological characteristics of the tested cell variants. CSCs showed the strongest response to the combination therapy approach, suggesting that they may represent more vulnerable cell variants to the tested treatment. Cisplatin-resistant cell lines could also be treated successfully with 5-ALA-PDT, whereas berbamine could enhance its efficacy in the cisplatin-resistant J82 LTT. These findings suggest that the combination treatment of 5-ALA-PDT and berbamine may serve as a promising approach to overcome therapeutic resistance in bladder cancer, particularly in cisplatin-resistant and CSC-enriched tumour types.

Approximately 70% of clear cell renal cell carcinoma (ccRCC) patients harbor von Hippel‒Lindau (VHL) deficiency, which drives pseudohypoxia and metabolic reprogramming. Here, we report a histone H4 lysine 12 lactylation (H4K12la)-fueled phosphoglycerate kinase 1 (PGK1)-lactate positive feedback loop that sustains glycolytic flux in VHL-deficient ccRCC and is pharmacologically disruptable by glucocorticoids. H4K12la is markedly elevated in ccRCC tissues and is associated with advanced pathological stage and unfavorable patient outcome. Integrative transcriptomic and epigenomic profiling revealed that VHL deficiency amplifies H4K12la deposition at accessible promoters, coupled to transcriptional activation of glycolytic and tumor-promoting programs, exemplified by PGK1. Through high-content drug screening, we identify glucocorticoids as effective suppressors of H4K12la, which act via glucocorticoid receptor-mediated transcriptional repression of glycolytic genes and consequent attenuation of lactate production. Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.