Gastric cancer remains a leading cause of cancer-related mortality worldwide. The classical Helicobacter pylori-centric paradigm of gastric carcinogenesis is being progressively expanded, as it is now recognized that the stomach harbors a complex and metabolically active microbial ecosystem whose compositional shifts fundamentally influence oncogenic progression. This review proposes a unifying dysbiosis-carcinogenesis-immune remodeling-therapeutic intervention (DCIT) framework to integrate the rapidly growing body of evidence linking gastric microbiota dysbiosis to malignancy. We survey the compositional landscape of the gastric microbiota across the Correa cascade, from healthy homeostasis through atrophic gastritis, intestinal metaplasia, and adenocarcinoma, and examine the ecological succession that releases niche constraints for oral commensals and nitrate-reducing taxa in advanced disease stages. We systematically evaluate four complementary mechanistic axes of microbial carcinogenesis: genotoxicity driven by bacterial effectors, chronic inflammation sustained by pattern recognition receptor signaling, epithelial barrier disruption facilitating bacterial translocation, and metabolic reprogramming of the gastric niche generating carcinogenic N-nitroso compounds and secondary bile acids. The review further examines how gastric microbiota remodels the tumor immune microenvironment through immune cell reprogramming, metabolite-mediated signaling, and checkpoint modulation, with direct implications for the efficacy of immune checkpoint inhibitor immunotherapy. The translational pipeline is evaluated from established H. pylori eradication regimens through probiotics, phage therapy, and fecal microbiota transplantation to emerging strategies that integrate microbiota modulation with chemotherapy and immunotherapy. Finally, we assess the methodological challenges of low-biomass gastric microbiome research, the integration of multi-omics platforms, and the critical evidence gaps that need to be addressed to realize the clinical potential of microbiota-targeted strategies for gastric cancer prevention and treatment.

A molecular analysis of pancreatic cyst fluid is revolutionizing the clinical management of pancreatic cysts. Yet, there remains need for ongoing correlation of molecular testing with surgical pathology. An ~70-year old male was found to have focal main pancreatic duct dilation up to 7 mm at the pancreatic head/neck on imaging without any discrete mass lesions. Duct fluid analysis found elevated carcinoembryonic antigen and decreased glucose level suggestive of intraductal papillary mucinous neoplasm (IPMN). Yet, molecular testing revealed no mutations. In the absence of a mass lesion, he was recommended surveillance. A year later, he had stable imaging and underwent repeat molecular testing, which revealed KRAS and GNAS mutations. He underwent pancreatoduodenectomy for suspected main duct IPMN. Final pathology revealed low-grade, multifocal pancreatic intraepithelial neoplasia, not IPMN. Ongoing assessment of concordance between molecular testing and postoperative pathology after pancreatectomy is needed to refine the multimodal diagnostic evaluation of pancreatic cysts.

Colorectal cancer (CRC) is a major global health burden, and chemotherapy resistance remains a major challenge to effective treatment. Increasing evidence indicates that the gut microbiota may contribute to variability in chemotherapy response in CRC through microbial metabolism, tumor-cell adaptation, immune regulation, and microbiota-derived metabolites. These processes can alter drug exposure, cellular stress responses, antitumor immunity, and metabolic conditions within the tumor-host ecosystem. In this review, we summarize current evidence on the mechanisms linking the gut microbiota to chemotherapy response in CRC, focusing on microbial drug metabolism, tumor-cell adaptation, immune and metabolic regulation, and microbial interactions with host signaling pathways. We also discuss emerging microbiome-based interventions, including probiotics, fecal microbiota transplantation, phage therapy, and targeted modulation of microbial functions, while considering the limitations of current evidence and challenges to clinical translation. Finally, we highlight future priorities, including causal validation of microbial functions, identification of robust biomarkers, and prospective evaluation of microbiome-informed patient stratification. This review provides an overview of current mechanistic evidence and the potential of microbiome-based approaches to improve chemotherapy response in CRC.

Hypoxia-pyroptosis-associated long noncoding RNAs (HP-lncRNAs) may contribute to cancer progression and treatment resistance, but their prognostic and mechanistic roles in lung cancer remain unclear. We conducted a systematic review and meta-analysis to evaluate their prognostic value and regulatory networks in lung cancer.

Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we systematically searched five scientific databases up to November 20, 2025, for studies evaluating HP-lncRNA expression and survival outcomes. Hazard ratios (HRs) were pooled by using random-effects models, with heterogeneity being assessed by I². Subgroup analyses examined histology, tumor stage, and study design. Mechanistic evidence and protein-interaction networks were also synthesized.

A total of 27 studies were included, with 14 providing quantitative data for meta-analysis. High expression of HP-lncRNA signatures was significantly associated with poorer overall survival (pooled adjusted HR = 1.50; 95% CI, 1.23-1.84), with a pronounced effect in lung adenocarcinoma (adjusted HR = 1.64; 95% CI, 1.34-1.99). Subgroup analyses supported a consistent adverse association across cohort designs and showed that the association remained evident in the advanced-stage subgroup (adjusted HR = 1.60; 95% CI, 1.44-1.77), although clear stage-specific effect modification was not demonstrated. Mechanistic evidence linked some lncRNAs to hypoxia-related regulation and others to pyroptosis-related signaling. Although direct evidence of a single lncRNA connecting both pathways is limited, findings support possible hypoxia-pyroptosis crosstalk. HIF-1a and caspase-1 emerged as central hub genes.

Our findings suggest that HP-lncRNA signatures may have prognostic relevance and therapeutic potential in lung cancer; however, the marked between-study heterogeneity indicates that further standardization and external validation are required before clinical application.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. As a predominant immune cell population in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a critical role in tumor progression and resistance to immune checkpoint inhibitors (ICIs). TAMs can promote either antitumor immunity or immunosuppression depending on their polarization status. Iron regulatory protein 2 (IRP2) is a key regulator of intracellular iron homeostasis and has been reported to be upregulated in several tumor types. However, the role of IRP2 in the TME remains unclear. This study revealed the previously unrecognized role of IRP2 in NSCLC progression and explored its potential as a TAM-directed therapeutic target linked to programmed death-ligand 1 (PD-L1) regulation. We found that IRP2 skewed TAMs toward an immunosuppressive state that promoted tumor cell proliferation and migration, and limited apoptosis. Furthermore, IRP2 may sustain PD-L1 expression in TAMs by limiting sphingosine kinase 1 (SphK1)-associated lysosomal degradation. In conclusion, our findings identify IRP2-dependent maintenance of the immunosuppressive TAM phenotype as a promising therapeutic target in NSCLC.

Cancer remains a major global health challenge, highlighting the urgent need to develop safer and more effective therapeutic drugs. Ginseng (Panax ginseng C.A. Mey.), as a medicinal plant widely used in traditional Chinese medicine, has attracted much attention for its extensive anticancer potential and a variety of biologically active ingredients (especially ginseng saponins and polysaccharides). This article reviews the latest research progress on the pharmacological activity and molecular mechanism of ginseng extract in cancer treatment, focusing on its inhibition of tumor growth, inducing cell apoptosis, inhibiting epithelial-mesenchymal transformation and metastasis, reshaping the tumor microenvironment, enhancing antitumor immunity, regulating metabolic reprogramming, and regulating epigenetics. In addition, this article also explores their potential to overcome multi-drug resistance and enhance the efficacy of traditional chemotherapy drugs. In recent years, a variety of drug delivery systems, including polymer nanoparticles, lipids, and micelles, have been developed to improve the bioavailability, stability, and tumor targeting of these compounds. This article also focuses on the current progress and challenges in clinical transformation, especially in the development and application of ginseng saponin preparations. In a word, this article provides a comprehensive review of ginseng-derived drugs from the perspective of pharmacology and translational medicine, and looks forward to the future direction of their reasonable development in cancer treatment.

Glioblastoma (GBM) is characterized by aggressive progression and profound immune evasion, yet the underlying mechanisms remain incompletely understood. Here, we identify the adaptor protein SH2B3 as a critical driver of immune evasion in glioblastoma and show that elevated SH2B3 expression is associated with higher glioma grade and poorer survival in public datasets and clinical data. Although SH2B3 modulation did not significantly affect GBM cell proliferation, migration, or invasion in vitro assays, it significantly altered tumorigenesis in vivo, with overexpression enhancing and knockdown suppressing tumor growth, suggesting that microenvironmental factors may contribute to the in vivo phenotype. We further show that SH2B3 promotes immune evasion at least in part by upregulating PD-L1 expression. Mechanistically, SH2B3 facilitates BRCC3-dependent removal of K63-linked polyubiquitin chains from the m⁶A reader IGF2BP2, thereby stabilizing IGF2BP2 and preventing its autophagy-lysosome-dependent degradation. The stabilized IGF2BP2 then enhances the stability and translation of m⁶A-marked PD-L1 transcripts through m⁶A-dependent transcript recognition. Collectively, our findings reveal a novel SH2B3/BRCC3/IGF2BP2 axis connecting protein deubiquitination and RNA epigenetics to PD-L1-mediated immune evasion, highlighting SH2B3 as a promising therapeutic target for glioblastoma immunotherapy.

Chemotherapy is one of the important clinical treatments for malignant tumors, but primary or acquired chemotherapy resistance significantly limits patient benefits. Programmed death ligand 1 (PD-L1) has been reported to be regulated by chemotherapy and to contribute to chemotherapy resistance. However, as a novel regulatory molecule of PD-L1, the relationship between CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) and chemotherapy resistance remains understudied. Here, we found that tumor CMTM6 and PD-L1 were upregulated by chemotherapy in clinical cancer patients, in vitro human or mouse tumor models, and in vivo mouse tumor models. PI3K-mTOR was the potential mechanism underlying this effect. CMTM6 deficiency could still reduce chemotherapy-induced tumor PD-L1 expression. And CMTM6 could promote tumor cell resistance to chemotherapy-induced apoptosis and growth arrest, which may be associated with p53. In vivo, both tumor and host CMTM6 and PD-L1 could promote resistance to chemotherapy, and tumor and host CMTM6 knockout could promoted antitumor immune responses during chemotherapy. Moreover, we developed and evaluated the antitumor effects of CMTM6&PD-L1-targeting adeno-associated virus (AAV), which effectively mobilized antitumor immunity and could be combined with chemotherapy. Our findings reveal that both tumor- and host-derived CMTM6 and PD-L1 are regulatory molecules of chemotherapy resistance and can serve as therapeutic targets for combination therapy with chemotherapy.

Esophageal carcinoma (EC) remains one of the most lethal malignancies, with a five-year survival rate of only 15-25% in advanced stages. Although immunotherapy including immune checkpoint inhibitors (ICIs) and antibody-based therapies have improved clinical outcomes, durable responses are confined to a minority of patients because primary and acquired resistance affect the majority. The tumor microenvironment (TME)-composed of immune cells, stromal cells, and the extracellular matrix-has emerged as a central driver of the immune resistance, wherein infiltrating immune cells and stromal cells form suppressive networks that impair cytotoxic immunity and foster tumor progression. However, a coherent framework linking clinical practice, TME-mediated resistance mechanisms, and therapeutic strategies remains lacking. In this review, we dissect the cellular and molecular basis of TME-driven immune resistance in EC, summarize established and emerging immunotherapies, and evaluate strategies to overcome treatment failure, including TME-targeted therapy, metabolic modulation, photodynamic therapy, and mechanism-guided combination approaches. These insights reframe immunotherapy resistance as a TME-driven process rather than a purely tumor-intrinsic defect, underscoring the need to concurrently target malignant cells and their surrounding immunosuppressive niche. Ultimately, elucidating TME heterogeneity and its dynamic evolution is essential to convert resistant EC into an immunotherapy-responsive disease and to guide precision combination strategies.

Introduction. [¹⁸F]FDG can be considered as PET tracer to determine whole-body staging in patients with locally advanced (LABC), metastatic, and recurrent breast cancer. Yet, previous studies demonstrated a lower amount of metabolic accumulation on [¹⁸F]FDG PET in case of oestrogen receptor (ER)-positive breast cancer. Consequently, given the lower metabolic accumulation, patients with ER-positive breast cancer might be at risk for underdiagnosis according to [¹⁸F]FDG PET. A novel PET tracer, [⁶⁸Ga]-fibroblast activation protein inhibitor (FAPI)-46, has shown promising results in breast cancer (re)staging. This single-centre prospective pilot study aims to explore the relative diagnostic accuracy of [⁶⁸Ga]-FAPI-46 compared to [¹⁸F]FDG in patients with ER-positive breast cancer and will provide the required information to support sample size calculation for a future validation study. Methods. In this study, 20 patients with ER-positive LABC, metastatic, or recurrent breast cancer will undergo the standard [¹⁸F]FDG PET exam and a [⁶⁸Ga]-FAPI-46 PET/CT and [⁶⁸Ga]-FAPI-46 PET/MRI exam. Histopathological confirmation will be obtained in cases of discordant or concordant (double-positive) findings, depending on clinical relevance and technical feasibility. The study will provide preliminary estimates of the relative accuracy of [⁶⁸Ga]-FAPI-46 PET when compared to [¹⁸F]FDG PET as well as the proportion of discordant findings and patients in whom a biopsy is feasible. Conclusions. The present single-centre prospective pilot study will characterize the potential of [⁶⁸Ga]-FAPI-46 PET to identify additional lesions not detected on a [¹⁸F]FDG PET exam in patients with ER-positive breast cancer to estimate an adequate sample size for a future validation study. Trial registration. This study was registered prospectively on ClinicalTrials.gov. Trial registration number: NCT06335069; Register date: 28 March 2024.