British Journal of Cancer

Lovell, Amy L.; Makamo, Nthongase; Veal, Gareth J.; Bernhardt, Melanie B.; Barr, Ronald; Gala, Rajul M.; Gordon, Erin; Ladas, Elena J.; Prasad, Maya; Rogers, Paul C.; Schoeman, Judy; Slone, Jeremy S.; Viani, Karina; Tissing, Wim J. E.; Huibers, Minke H. W.

doi: 10.1038/s41416-025-03023-3pmid: 40571762

Malnutrition (undernutrition or overweight/obesity) might significantly impact the pharmacokinetics and pharmacodynamics of antineoplastic drugs in children and adolescents (<21 years). A comprehensive systematic literature search was performed on MEDLINE (PubMed), EMBASE, Web of Science, Scopus, ProQuest, Cochrane Trials, and Cochrane Reviews. Databases were searched up to 30 September 2024. Of 4186 articles identified, 150 full texts were evaluated and 12 selected for inclusion. Eight additional articles were identified following a panel review and 6 included, resulting in a total of 18 articles for data extraction. Relevant pharmacokinetic parameters were described for mercaptopurine, vincristine, anthracyclines, methotrexate, busulfan, bevacizumab, and crizotinib. Due to the heterogeneity and limited number of studies per antineoplastic drug, formal statistical analysis or meta-analysis was not appropriate. Variations in the definition of nutritional status, dosing strategies, and type of pharmacokinetic analyses were observed; therefore, no dosing recommendations could be made. With the increasing childhood cancer burden in LMIC, high prevalence of undernutrition, and the global burden of childhood obesity, there is an urgent need for more research in this area. Prospective studies should incorporate uniform definitions and standardised pharmacological approaches to optimise treatment options for children with cancer globally.Systematic literature review registrationPROSPERO: (reference: CRD42023435261)

Kallionpää, Roope A.; Martikkala, Eija; Haapaniemi, Pekka; Karppinen, Sanna-Maria; Riihilä, Pilvi; Rokka, Anne; Leivo, Ilmo; Pihlajaniemi, Taina; Peltonen, Sirkku; Peltonen, Juha

doi: 10.1038/s41416-025-03055-9pmid: 40394150

BackgroundCutaneous neurofibromas (cNFs) are the hallmark of the tumor-predisposition syndrome neurofibromatosis 1 (NF1). While cNFs are always benign, they markedly decrease quality of life in individuals with NF1. Understanding the differences between cNFs and the skin is essential for developing treatments for cNFs.MethodsWe collected 15 cNFs from four NF1 individuals and used mass spectrometry to compare the tumor tissue with the skin overlying each tumor. Data were analyzed based on Gene Ontology (GO) terms.ResultsThe expression patterns of the Schwann cell marker S100B and several keratins confirmed successful dissection of cNF tissue from the overlying skin. Hierarchical clustering showed extensive overlap between the tumor and skin samples in three out of four individuals, suggesting high overall similarity between the two tissue types. Based on the analysis of the GO terms, cNFs were associated with decreased expression of proteins related to cell proliferation, extracellular matrix remodeling, angiogenesis and cellular metabolism.ConclusionThe cNFs are relatively quiescent, consistent with their benign nature and limited growth potential. The development of pharmacological therapy for cNFs requires overcoming the high similarity between cNFs and the overlying skin. The present dataset can serve as a resource for future research on cNFs.

Cui, Kele; Hu, Shouxin; Zha, Yanfang; Ding, Keshuo; Wei, Haiming; Cheng, Min; Mei, Xinyu

doi: 10.1038/s41416-025-03065-7pmid: 40437020

BackgroundAlthough extensive evidence indicates that tissue-resident natural killer (trNK) cells are closely related to the development and clinical outcomes of various tumours, their roles in esophageal cancer remain obscure.MethodsTumour tissues collected from 54 esophageal squamous cell carcinoma (ESCC) patients during surgery and human ESCC tissue arrays including samples from 258 patients were subjected to analyse the phenotype and functions of immune cells.ResultsWe observed a population of CD49a+ NK cells with a CD103hiCD69hi resident phenotype predominantly within the CD56bright NK cell subset in the intratumoral tissue of ESCC patients. These CD49a+ trNK cells, characterised by high expression of inhibitory receptors (TIM-3, CD244, TIGIT, PD-1), reduced cytotoxic potential (lower CD16, granzyme B, and perforin), and elevated secretion of IFN-γ and TGF-β, exhibited an exhausted and regulatory phenotype. Their presence was associated with poor prognosis in early-stage ESCC, but not in advanced stages. Mechanistically, these cells were found to enhance the immunosuppressive tumour environment by increasing MDSCs through GM-CSF secretion, thereby facilitating tumour progression.ConclusionsOur research reveals that tumour-infiltrated CD49a+ NK cells exhibit exhausted and regulatory profile, capable of inducing the accumulation of MDSCs by secreting GM-CSF, and predict poor clinical outcomes in early-stage ESCC patients.trNK cells in esophageal tissues exhibit antitumor potential via degranulation-mediated elimination of cancer cells, thereby performing immune surveillance. However, during tumour progression, upregulation of immune checkpoint molecules (e.g., TIM3 and CD244) on trNK cells results in reduced cytotoxic activity and an exhausted phenotype. Exhausted trNK cells further enhance the immunosuppressive tumour microenvironment by promoting MDSCs accumulation through GM-CSF secretion, ultimately facilitating tumour progression. The graph was created with BioRender.com.[graphic not available: see fulltext]

Bajaj, Upasana; Das, Dipanwita; Leung, Jia Yu; Binti Abdul Rashi, Nurul Fateha; Taneja, Reshma

doi: 10.1038/s41416-025-03066-6pmid: 40467997

BackgroundRhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. When metastatic, survival of children with RMS is less than 20% and has remained unchanged over two decades. No targeted drug therapy is available for these cancers. Genomic analysis has revealed a low incidence of somatic mutations in RMS. Epigenetic modifiers thus play important roles in driving oncogenesis. In this study, we examined the role of EHMT1 in fusion- negative embryonal rhabdomyosarcoma (ERMS), the most frequent subtype of RMS.MethodsWe performed transcriptomic and phenotypic analysis in vitro and in vivo using EHMT1 depleted cells as well as that of its target gene SOX8.ResultsEHMT1 was found to enhance migration and invasion of ERMS cells in vitro and metastasis in vivo. SOX8, a transcription factor that has key roles in cellular motility was significantly decreased upon EHMT1 loss. Consistently, SOX8 depletion phenotypically mimicked EHMT1 loss. Moreover, RNA Sequencing of SOX8 depleted cells showed down regulation of several integrin genes. Mechanistically, EHMT1 was found to upregulate SOX8 via regulation of BRD4 expression, and consequently increased BRD4 occupancy at the SOX8 promoter.ConclusionOur study reveals a novel EHMT1-SOX8 axis that mediates metastasis in ERMS.

Sorbye, Halfdan; Hjortland, Geir Olav; Vestermark, Lene Weber; Ladekarl, Morten; Svensson, Johanna; Sundlöv, Anna; Janson, Eva Tiensuu; Garresori, Herish; Hofsli, Eva; Kersten, Christian; Elvebakken, Hege; Pfeiffer, Per; Morken, Siren; Assmus, Jorg; Lothe, Inger Marie Bowitz; Tabaksblat, Elizaveta; Knigge, Ulrich; Couvelard, Anne;

Zhang, Zhen; Jin, Xingyu; Yin, Qiang; Li, Peng; Sun, Zengfeng; Li, Wenliang; Liu, Qun; Zhang, Xiaohui; Wang, Peng; Piao, Yingzhe; Lu, Yalin; Li, Lianwang; Yi, Kaikai; She, Chunhua; Ma, Li; Zhang, Jiangyan; Jin, Xun;

Noringriis, Inge Mansfield; Donia, Marco; Madsen, Kasper; Schmidt, Henrik; Haslund, Charlotte Aaquist; Bastholt, Lars; Svane, Inge Marie; Ellebaek, Eva

doi: 10.1038/s41416-025-03048-8pmid: 40419744

BackgroundA substantial number of patients with metastatic melanoma (MM) treated with anti-PD-1 monotherapy have initial stable disease (SD), yet the real-world prognosis of these patients remains unclear.MethodsIn this nationwide cohort study, we analysed real-world outcomes of patients with MM treated with pembrolizumab in Denmark. Focusing on patients with initial SD, we assessed best overall response (BOR), progression-free survival (PFS), and overall survival (OS) and identified predictors of survival in multivariable analyses.ResultsOut of 1048 included patients, 233 (22.2%) had initial SD with a median PFS and OS of 14.7 and 50.1 months. Subsequent partial response (PR) or complete response (CR) was developed by 44 (18.9%) and 52 (22.3%) patients showing significantly improved PFS compared to patients with continued SD (PR: HR 0.52, 95% CI 0.34–0.81, p = 0.003; CR: HR 0.15, 95% CI 0.07–0.32, p < 0.001) and survival rates comparable to patients with initial PR and CR, respectively. Furthermore, 49 (21.0%) patients showed continued disease control (median follow-up of 82.3 months). For 51.0% of these patients, the last dose of pembrolizumab was administered during SD with a median treatment duration of 12.4 months.ConclusionsOf patients with initial SD, 40% developed a subsequent objective response with improved long-term prognosis comparable to patients with initial response. More than 20% exhibited continued disease control.

Gurney, Jason; Davies, Anna; Stanley, James; Dunn, Alex; Cameron, Laird; Costello, Shaun; Dawkins, Paul; Koea, Jonathan; Whitehead, Jesse; Jackson, Christopher GCA

doi: 10.1038/s41416-025-03071-9pmid: 40481177

BackgroundLung cancer survival can be improved through treatment, but several factors can influence the pattern of treatment received by a given individual. Using national-data across the lung cancer treatment pathway, here we describe treatment variation according to clinical and sociodemographic factors.MethodsWe used national health data linked to the New Zealand Cancer Registry (NZCR) to describe variation in surgery, radiation therapy and systemic therapy for all lung cancers from 2012–2019 (n = 18,081), stratified by ethnicity, cancer stage, area deprivation, rurality status and comorbidity. Crude and adjusted descriptive analysis were used, including marginally standardised risk estimates from logistic regression.ResultsThe most common treatment was radiation therapy, either in isolation or combined with systemic therapy (combined total: crude 37%, fully-adj. 40%). Systemic therapy was the next most common treatment modality (crude 28%, fully-adj. 33%). Surgery was the least common treatment modality, used in around 15% of the cohort (crude 18%, fully-adj. 15%). Once adjusted for other factors, treatment access varied somewhat by ethnicity. Increasing stage of disease reduced the likelihood of surgery and increased the likelihood of radiation and systemic therapy. Increasing deprivation marginally reduced access to surgery, while rurality appeared to have no independent impact. Increasing comorbidity reduced the overall likelihood of treatment, systemic therapy alone, and radiation therapy + systemic therapy in combination.DiscussionWe found variation in the pattern of cancer treatment received according to factors including ethnicity, stage, deprivation and comorbidity, but no clear independent variation by rurality.

Papanikolaou, Christina; Economopoulou, Panagiota; Spathis, Aris; Kotsantis, Ioannis; Gavrielatou, Niki; Anastasiou, Maria; Moutafi, Myrto; Kyriazoglou, Anastasios; Foukas, George-Romanos P.; Lelegiannis, Ioannis M.; Rimm, David; Panayiotides, Ioannis; Foukas, Periklis;

Jing, Yanyun; Wu, Yangzhe; Hu, Qinglin; Wu, Wenfeng; Li, Dang; Hu, Wenhao; Li, Heming; Fu, Minggang; Huang, Xin; Hu, Yi

doi: 10.1038/s41416-025-03045-xpmid: 40437021

Backgroundγδ T cells have emerged as pivotal regulators within the breast cancer tumour microenvironment (TME) and represent a promising therapeutic strategy for late-stage and metastatic breast cancer. In recent years, our research has focused on leveraging allogeneic Vγ9Vδ2 T cells as a novel approach to treat advanced cancers, including triple-negative breast cancer (TNBC). However, the varying clinical outcomes of this therapy have prompted us to investigate the diverse roles of γδ T cells within the TNBC microenvironment and to explore strategies for enhancing therapeutic efficacy through microenvironmental remodelling.MethodsData from TCGA, publicly available scRNA-seq datasets and a series of experiments including flow cytometry, atomic force microscopy, confocal laser scanning microscopy, mouse model and others were applied to examine the functional heterogeneity of γδ T cells in TNBC, non-TNBC, and healthy individuals.Resultsγδ T cells serve as predictive markers of better prognosis in breast cancer. In TNBC tumours, γδ T cells exhibited heightened expression of genes linked to both effector and inhibitory molecules, alongside a significant upregulation of glycolytic activity—patterns not observed in non-TNBC or normal breast tissues. Further analysis demonstrated that hypoxic conditions in the TNBC microenvironment likely contribute to these metabolic changes, leading to upregulation of inhibitory checkpoints and downregulation of effector functions in γδ T cells. Importantly, we showed that suppressing HIF-1 signalling using PX478 enhanced the antitumor efficacy of Vδ2+γδ T cell therapy in TNBC-bearing mice.DiscussionThis work underscores that remodelling the hypoxic TNBC microenvironment can restore the antitumor activity of Vγ9Vδ2 T cell therapy. Our findings offer a compelling new adjuvant strategy to improve the outcomes of Vγ9Vδ2 T cell-based therapies for advanced breast cancer treatment.[graphic not available: see fulltext]