Medical Oncology最新文献

{"title":"Tumor microenvironment and gut microbiome in immunotherapy resistance in gastric cancer: clinical questions, biological mechanisms, and evidence-based therapeutic perspectives.","authors":"Tamotsu Sagawa, Masahiro Hirakawa, Hiroyuki Nagashima, Koshi Fujikawa","doi":"10.1007/s12032-026-03434-z","DOIUrl":"10.1007/s12032-026-03434-z","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have improved systemic therapy for advanced gastric and gastroesophageal junction cancer, yet primary and acquired resistance remain common and are incompletely explained by established tumor biomarkers. This narrative review evaluates the connected roles of the tumor microenvironment (TME), host immunity, and the gut microbiome in shaping ICI resistance in gastric cancer. We performed a structured PubMed search through 28 August 2026 and prioritized gastric cancer-specific clinical and translational evidence, supplemented by systematic reviews, meta-analyses, and mechanistically relevant studies from other tumor types when necessary. Within the gastric cancer TME, cancer-associated fibroblasts, myeloid cells, regulatory T cells, extracellular matrix remodeling, hypoxia, angiogenesis, and T-cell exhaustion can promote immune exclusion or dysfunction. Microbial diversity, microbial metabolites, antibiotics, proton pump inhibitors, defined live biotherapeutics, fecal microbiota transplantation, and diet may influence systemic antitumor immunity, but most human evidence is retrospective, cross-sectional, or derived from non-gastric cancers. Clinically, antibiotic stewardship, reassessment of unnecessary acid suppression, and nutritional optimization are reasonable supportive measures, whereas routine probiotic supplementation, Clostridium butyricum MIYAIRI 588 for ICI sensitization, and fecal microbiota transplantation remain investigational in gastric cancer. Future studies should integrate longitudinal exposures, serial TME profiling, stool metagenomics, medication use, nutritional status, and clinical outcomes. The TME-gut microbiome axis is therefore a biologically plausible framework for biomarker-guided research, but current evidence does not justify empiric microbiome-directed anticancer therapy in gastric cancer.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The circMTCL1/miR-145-5p/BMP3 axis suppresses colorectal cancer cell growth by mediating the MAPK signaling pathway.","authors":"Liyuan Liu, Dan Jiang, Yongcun Jia, Yuqing Dong, Wei Zhao","doi":"10.1007/s12032-026-03414-3","DOIUrl":"10.1007/s12032-026-03414-3","url":null,"abstract":"<p><p>Circular RNAs play key roles in colorectal cancer (CRC). Here, we examine the function and underlying mechanism of circMTCL1 in CRC. The expression of circMTCL1 in CRC tissues and cell lines were detected by quantitative real-time PCR (qRT-PCR). The function of circMTCL1 was elucidated through overexpression and knockdown studies. Furthermore, a combination of Fluorescence in situ hybridization (FISH), nuclear-cytoplasmic fractionation, RNA immunoprecipitation (RIP), qRT-PCR, Western blotting, and dual-luciferase reporter assays was employed to elucidate the tumor-suppressive mechanism of circMTCL1 in CRC. circMTCL1 was significantly downregulated in CRC tissues compared to adjacent normal tissues, showing a 17.08-fold decrease (P < 0.001). It functioned as a competing endogenous RNA (ceRNA) by specifically binding to miR-145-5p, thereby modulating the expression of Bone Morphogenetic Protein 3 (BMP3). Overexpression of circMTCL1 markedly inhibited the proliferation, migration, and invasion of CRC cells, resulting in a 3.76-fold decrease in proliferation (P < 0.001), and 1.58-fold and 2.00-fold decreases in migration and invasion, respectively (P < 0.001). Furthermore, circMTCL1 overexpression upregulated BMP3 expression by 1.60-fold (P < 0.001). Further investigation revealed that circMTCL1 regulates tumor progression by suppressing the activation of the MAPK signaling pathway. circMTCL1 acts as a tumor suppressor in CRC. Its mechanism likely involves sponging miR-145-5p to regulate BMP3 expression and modulating the MAPK signaling pathway. These findings provide a new perspective on the pathogenesis of CRC and identify a potential therapeutic target for clinical intervention.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YTHDF2 drives malignant progression in cutaneous melanoma through m⁶A-dependent HMOX1-mediated ferroptosis.","authors":"Da Gu, Yulin Sun, Jinpeng Sun, Weiting Kang, Huanmin Lou, Xiaojing Li","doi":"10.1007/s12032-026-03427-y","DOIUrl":"10.1007/s12032-026-03427-y","url":null,"abstract":"<p><p>N6-methyladenosine (m6A) modification plays a critical role in eukaryotic mRNA and is significantly associated with cutaneous melanoma. This study investigated the role of the m6A-binding protein YTHDF2 in the pathogenesis of cutaneous melanoma and its potential therapeutic applications. Analyses of public databases indicated that YTHDF2 exhibited elevated expression in various cancers, including cutaneous melanoma, where its levels positively correlated with PD-L1 and negatively correlated with immune and stromal scores. Functionally, the downregulation of YTHDF2 in melanoma cells suppressed proliferation and increased the population of Annexin V/PI--positive cells, an effect that was rescued by the ferroptosis inhibitor, highlighting YTHDF2's involvement in ferroptosis regulation. YTHDF2 knockdown resulted in increased intracellular Fe²⁺ levels, malondialdehyde, reactive oxygen species, and lipid peroxidation, alongside a reduction in glutathione-effects that were reversed upon ferroptosis inhibition. In vivo studies corroborated the regulatory role of YTHDF2 in ferroptosis. Mechanistically, integrated RNA-seq and RIP-seq analyses demonstrated that YTHDF2 could bind to m6A on HMOX1 transcripts, destabilizing its mRNA and thus regulating HMOX1 expression. Moreover, metformin was shown to inhibit YTHDF2 expression, promoting ferroptosis in melanoma cells. In summary, YTHDF2 modulates ferroptosis in melanoma through the regulation of m6A-dependent HMOX1 mRNA stability, suggesting it as a promising therapeutic target. The capacity of metformin to suppress YTHDF2 indicates its potential utility in hindering melanoma progression.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host chromatin architecture in HPV-driven cervical cancer: molecular mechanisms and therapeutic resistance.","authors":"Katsuyoshi Kumagai, Yasuhiro Suzuki, Kei Kitahara, Ayumi Chiba, Hiroaki Yajima","doi":"10.1007/s12032-026-03445-w","DOIUrl":"10.1007/s12032-026-03445-w","url":null,"abstract":"<p><p>Persistent infection with high-risk human papillomavirus (HPV) is the principal etiologic driver of cervical cancer. However, HPV status and E6/E7-mediated disruption of the p53/RB axis do not fully explain why HPV-associated lesions differ in persistence, malignant progression, therapeutic response, and relapse. This review examines how host chromatin architecture and related transcriptional programs may contribute to the stabilization of malignant cell states following HPV-mediated checkpoint disruption. We discuss evidence linking HPV persistence and integration to epigenetic permissiveness, three-dimensional genome organization, enhancer-promoter rewiring, cohesin dynamics, and WAPL-associated chromatin regulation. Particular attention is given to how these mechanisms may influence MYC/E2F-centered proliferative output and cooperate with context-dependent signaling and tumor microenvironmental adaptation to contribute to treatment tolerance and resistant malignant states. We also consider how chromatin-informed biomarkers, public datasets, perturbation-guided prioritization, authenticated cervical cancer cell lines, organoids, and patient-derived models can be used to evaluate therapeutically relevant vulnerabilities. By integrating viral oncogenesis with host genome regulation and adaptive resistance, this review proposes a conceptual and experimentally testable framework for stratifying HPV-driven cervical cancer and prioritizing candidate intervention nodes.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis and tumor microenvironment: orchestrating therapy resistance, immune evasion, and metastatic events.","authors":"Mohammad Fahad Ullah","doi":"10.1007/s12032-026-03432-1","DOIUrl":"10.1007/s12032-026-03432-1","url":null,"abstract":"<p><p>Ferroptosis, an iron-dependent form of regulated cell death characterized by accumulation of lethal lipid peroxides, has emerged as a critical mechanism in cancer biology with significant implications for therapy and metastasis. This distinct mode of cell death is orchestrated through multiple molecular pathways, including the system Xc⁻/glutathione (GSH) /glutathione peroxidase 4 (GPX4) axis, iron metabolism dysregulation via transferrin receptor 1 (TFR1) and ferritin, and lipid remodeling through acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated incorporation of polyunsaturated fatty acids into membrane phospholipids. Unlike apoptosis, ferroptosis represents a unique vulnerability in cancer cells due to their elevated iron dependency, making it an attractive therapeutic target. However, the complex interplay between ferroptosis and the tumor microenvironment (TME) creates a double-edged sword that can either suppress or promote tumor progression. Recent evidence demonstrates that distinct cell populations within the TME exhibit differential sensitivities to ferroptosis, with profound consequences for tumor evolution. Mechanistically, cancer-associated fibroblasts activate the TGF-β/SMAD3/ATF4 signaling axis to upregulate sulfur transfer pathways, secreting cysteine that supports tumor cell GSH synthesis and GPX4 activity, thereby conferring ferroptosis resistance. This metabolic cross-feeding exemplifies how stromal cells create a protective niche that sustains tumor survival under oxidative stress. Additionally, exosome-mediated communication within the TME plays a pivotal role in regulating ferroptosis to facilitate metastasis, immune escape, and drug resistance. Studies have also examined how ferroptosis influences epithelial-mesenchymal transition and metastatic dissemination, while addressing the paradoxical role of ferroptosis in both promoting anti-tumor immunity and potentially suppressing immune responses depending on TME context. This review explores the multifaceted crosstalk between ferroptosis and various TME components, including cancer-associated fibroblasts, immune cells, stromal cells, and extracellular matrix elements. Moreover, ferroptosis-driven mechanisms underlying resistance to chemotherapy, radiotherapy, targeted therapies, and immunotherapy are discussed along the emerging therapeutic strategies that leverage ferroptosis induction to effectively target therapy-resistant and metastatic tumors.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of Coumarin in the anti-liver cancer activity by promoting NK cell activation.","authors":"Jincai Wen, Yuanyuan Guo, Xianling Wang, Yingjie Xu, Zongliang Lu, Qiaodi Liu, Xiaoyan Zhan, Xiaohe Xiao, Zhaofang Bai","doi":"10.1007/s12032-026-03413-4","DOIUrl":"10.1007/s12032-026-03413-4","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to elucidate the molecular mechanisms by which Coumarin exerts anti-liver cancer effects via natural killer (NK) cell activation. We investigated whether Coumarin inhibits liver cancer progression by enhancing NK cell effector functions, providing novel strategies for immunotherapy.</p><p><strong>Materials and method: </strong>In vitro, Sophora tonkinensis extract were screened in NK-92 cells. Cytokines (e.g., IFN-γ) were measured by ELISA; granzyme B and perforin levels were assessed via western blot and qPCR. Flow cytometry analyzed surface receptors. Findings were verified in primary human NK cells. In vivo, an H22 hepatocellular carcinoma syngeneic mouse model evaluated tumor growth. Immune cell infiltration in spleen and tumor tissues was quantified by flow cytometry and qPCR. Transcriptome sequencing and Seahorse metabolic analysis explored underlying mechanisms.</p><p><strong>Result: </strong>Coumarin significantly promoted NK cell activation. Synergizing with IL-12, it upregulated IFN-γ, granzyme B, and perforin transcription and enhanced their secretion and protein expression in both NK-92 and primary human NK cells. In vivo, Coumarin effectively inhibited H22 tumor growth, significantly reducing tumor volume. Flow cytometry revealed increased infiltration of NK cells and CD8⁺ T cells in tumor and spleen tissues. Transcriptomic analysis identified 194 upregulated and 67 downregulated genes, enriched in energy metabolism pathways. Seahorse analysis revealed that Cu significantly increased oxygen consumption rate (OCR), suggesting its ability to effectively restore energy supply in NK cells.</p><p><strong>Conclusion: </strong>Cu potentiates IL‑12-induced NK cell activation, accompanied by increased IFN-γ secretion and upregulated granzyme B and perforin expression. Cu inhibits hepatocellular carcinoma growth by improving NK cell cytotoxic function, remodeling the tumor immune microenvironment, and enhancing mitochondrial bioenergetic activity in NK cells. The present study preliminarily reveals the immunological and metabolic phenotypic mechanisms underlying the anti-tumor activity of coumarin. Notably, the current data only demonstrate elevated mitochondrial respiratory capacity without confirming comprehensive metabolic reprogramming or the direct molecular targets of coumarin. Collectively, these findings support that coumarin serves as a promising preclinical natural product candidate for liver cancer immunotherapy.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in discriminating prostate cancer from benign prostatic diseases in the pre-biopsy population.","authors":"Zijie Nie, Tianyi Zhu, Yichu Chen, Wei Zhang, Lingling Wu","doi":"10.1007/s12032-026-03424-1","DOIUrl":"10.1007/s12032-026-03424-1","url":null,"abstract":"<p><p>Prostate cancer (PCa) remains one of the most prevalent malignancies and a major cause of cancer-related deaths among men worldwide. Current pre-biopsy evaluation relies primarily on serum prostate-specific antigen (PSA) testing and multiparametric MRI (mpMRI), but both approaches have limited specificity, particularly in the diagnostic gray zone (PSA 4-10 ng/mL and/or equivocal MRI findings such as Prostate Imaging Reporting and Data System (PI-RADS) category 3 lesions). In this setting, overlap between PCa and benign prostatic diseases frequently leads to unnecessary biopsies. This unmet clinical need has driven the development of novel diagnostic strategies designed to better discriminate PCa from benign prostatic diseases before biopsy. In this review, we provide a comprehensive overview of recent advances in non-invasive diagnostic strategies, including liquid-based molecular biomarkers, advanced imaging modalities, and multimodal integrative frameworks. These advances may improve diagnostic accuracy, reduce unnecessary biopsies, and support personalized risk stratification and biopsy decision-making. Moreover, we highlight the paradigm shift from single-parameter screening to multimodal integration, including artificial intelligence-based approaches in early PCa screening. Overall, these non-invasive strategies may help reduce diagnostic uncertainty in the gray zone and support more precise and personalized biopsy decision-making.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TFEB promotes the progression of t(6; 11) translocation renal cell carcinoma by upregulating LINC00612 expression.","authors":"Hai-Yan Ni, Xiao-Xun Zhang, Xin-Ran Wang, Jing Ma, Xiao-Jing Yu, He-Qin Zhan","doi":"10.1007/s12032-026-03411-6","DOIUrl":"10.1007/s12032-026-03411-6","url":null,"abstract":"<p><p>T(6;11) translocation renal cell carcinoma (RCC) is a distinct renal tumor distinguished by the generation of Alpha-TFEB fusion gene. TFEB is highly expressed in this subtype and may drive its progression. However, its underlying mechanism remains incompletely elucidated. The current study is intended to explore whether TFEB promotes the progression of t(6;11) translocation RCC by regulating long intergenic non-protein coding RNA (LINC)00612 expression. HK-2-TFEB and Caki-2-TFEB were stably transfected cell lines with Alpha-TFEB fusion gene, which were successfully established in our research group's previous work. Western blotting was carried out to assess TFEB protein expression, and qRT-PCR was employed to measure LINC00612, microRNA (miR)-31-5p and CTNNB1 expression levels. Bioinformatics analysis, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were employed to validate the interactions between TFEB and LINC00612, LINC00612 and miR-31-5p, as well as miR-31-5p and CTNNB1. Wound healing, CCK-8 and invasion assays were used to verify the effects exerted by LINC00612 downregulation and upregulation, as well as CTNNB1 downregulation on the biological functionalities of cells. Experiments carried out in vivo were designed to assess the effects of TFEB, LINC00612 and miR-31-5p on tumor growth. Western blotting showed high expression of TFEB in HK-2-TFEB and Caki-2-TFEB cells compared to their respective control cells. qRT-PCR revealed enhanced expression of LINC00612, decreased miR-31-5p expression and increased expression of CTNNB1 in HK-2-TFEB and Caki-2-TFEB cells. Dual-luciferase reporter and ChIP experiments confirmed that TFEB specifically bound to the promoter of LINC00612. LINC00612 overexpression in HK-2 cells enhanced cell proliferative capacity, migratory activity, and invasive potential, while its knockdown in HK-2-TFEB cells suppressed these cellular processes. LINC00612 was shown to have targeted binding to miR-31-5p, and miR-31-5p was verified to target CTNNB1. In vivo experiments demonstrated that either TFEB or LINC00612 overexpression promoted tumor growth, whereas overexpression of miR-31-5p inhibited tumor growth. Our findings suggested that overexpression of TFEB upregulated LINC00612 expression and LINC00612 competitively inhibited miR-31-5p, which directly targeted the downstream gene CTNNB1, ultimately promoting tumor progression. TFEB/LINC00612/miR-31-5p axis may be a new molecular therapeutic target for t(6;11) translocation RCC patients.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of intratumor heterogeneity on outcome and resistance to therapy in primary breast cancer: a systematic review.","authors":"Aria Dianati, Andre Dekker, Anke Wesselius, Leonard Wee","doi":"10.1007/s12032-026-03426-z","DOIUrl":"10.1007/s12032-026-03426-z","url":null,"abstract":"<p><p>Intratumor heterogeneity (ITH), the coexistence of diverse subclones within a single tumor, may pose a major challenge to effective chemotherapy in breast cancer. This cellular diversity contributes to treatment failure, residual disease, and early relapse by enabling tumor adaptation and therapeutic resistance. Although increasingly recognized as a critical feature of breast cancer biology, it remains under-investigated and has not yet been integrated into routine clinical care. This review synthesizes current evidence on the role of ITH in chemotherapy resistance in primary breast cancer. Following PRISMA guidelines, we searched MEDLINE via PubMed, Web of Science, and Scopus through June 2026. Twelve studies met the inclusion criteria. Data were extracted on tumor subtypes, study design, ITH assessment modality (genomic, transcriptomic, radiomic, or immunologic), sampling method, treatment type, and outcomes. Among the 12 included studies, covering triple-negative, HER2-positive, and mixed breast cancer cohorts, high or increasing ITH, assessed using molecular or imaging-based methods, was associated with reduced sensitivity to chemotherapy. Proposed mechanisms underlying resistance included clonal selection, transcriptional plasticity, immune exclusion, and phenotypic drift. Radiomic and MRI-derived features may provide additional predictive value beyond molecular classifiers, and integrated radiomic-genomic models outperformed either modality alone in identifying patients with poor treatment response. In conclusion, current evidence suggests that ITH may be associated with chemotherapy resistance in primary breast cancer through several biological mechanisms. Integrating radiomic and imaging-based assessments with molecular profiling has the potential to improve the prediction of treatment response and facilitate monitoring of changes in tumor heterogeneity during therapy, although further prospective validation is needed before routine clinical implementation.Protocol Registration Number at PROSPERO: CRD42024533885.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ketogenic diet as a systems-level immunometabolic sensitization strategy in cancer therapy: integrating metabolism, immune reprogramming, microbiome dynamics, and epigenetic regulation.","authors":"Muhammad Shaheer Mannan, Muhammad Waqas Khan, Muhammad Abdul Haseeb Khan, Ahmed Javed, Syed Mujtaba Hussain, Hudda Adil","doi":"10.1007/s12032-026-03425-0","DOIUrl":"10.1007/s12032-026-03425-0","url":null,"abstract":"<p><p>The ketogenic diet (KD) is increasingly being recognized as more than a simple metabolic intervention in cancer therapy. Emerging evidence suggests that KD may function as a systems-level immunometabolic sensitization strategy capable of enhancing therapeutic responsiveness through interconnected biologic mechanisms. Modern cancer therapies, including chemotherapy, targeted therapy, radiotherapy, and immunotherapy, are often limited by tumor adaptability and immune suppression. Tumors shift metabolism via the Warburg effect and fuel switching, promoting resistance under hypoxic and nutrient stress. KD is a high-fat and low-carb eating plan that increases ketone bodies such as β-hydroxybutyrate while lowering glucose availability. Under ketogenic conditions, cancer cells reduce glycolytic flux, while immune cells can oxidise ketones to sustain mitochondrial function and effector activity. KD also remodels the gut microbiome and induces epigenetic regulation through histone deacetylase inhibition. These combined effects may enhance chemotherapy, radiotherapy, targeted therapy, and immunotherapy by inducing metabolic stress, improving immune cell fitness, and altering tumour microenvironment signaling. Importantly, KD may function not as a standalone treatment but as a therapy-sensitization platform. However, current evidence remains preliminary and heterogeneous, and further mechanistic investigations and well-designed prospective clinical trials are necessary to determine optimal patient selection and long-term safety.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":"43 11","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}