Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and responds poorly to immune checkpoint inhibitors. Lactate is abundant in the tumor microenvironment and is associated with immune evasion. This study examined the regulatory role of lactate and evaluated metabolism-immunity targeting strategies in PDAC. We used PDAC cell models exposed to lactate and xenograft mice, applying N1-methyladenosine RNA immunoprecipitation, ribosome profiling, and transcriptome analyses to examine lactate’s effects via the TRMT6-SIRT5 axis. The efficacy of CDK4/6 inhibitors combined with lactate metabolism blockers was also tested. Lactate significantly enhanced N1-methyladenosine RNA modification by TRMT6, increasing translation of key metabolic enzymes and driving reprogramming. It activated SIRT5-mediated desuccinylation, boosting TCA cycle enzyme activity and oxidative metabolism. Lactate upregulated PD-L1 via the TRMT6-SIRT5 axis, enhancing CDK4/6 signaling and immune evasion. Combining lactate blockers with CDK4/6 inhibitors reduced PD-L1 expression, restored T cell function, and improved anti-PD-1 therapy efficacy in mice. Lactate may promote metabolic reprogramming and immune evasion in PDAC through the TRMT6-SIRT5 axis, linking metabolism, epigenetic regulation, and antitumor immunity. Combining CDK4/6 inhibition with lactate blockade may provide a rationale for improving immunotherapy responses in pancreatic cancer.

Xenin, a 25-amino acid peptide hormone predominantly secreted by intestinal K cells, demonstrates evolutionary conservation with neuropeptides such as xenopsin and neurotensin. Functionally, it engages neurotensin receptor 1 (NTSR1) to regulate appetite via hypothalamic signaling pathways and modulates glucose homeostasis through synergistic interactions with incretin hormones. Preclinical studies highlight its dual role in suppressing appetite and enhancing pancreatic β-cell survival, while a single pilot human study suggests xenin-25 may delay gastric emptying and attenuate postprandial glucose excursions; however, these data await independent confirmation. Native xenin, however, is constrained by rapid proteolytic degradation and limited bioavailability. Advances in peptide engineering, including C-terminal truncation, site-directed amino acid substitution, and lipidation, have generated analogues that exhibit prolonged metabolic activity in rodent models, with plasma half-life extended from minutes to hours. In murine models of metabolic dysfunction, these derivatives enhance insulin secretion, improve glycaemic profiles and restore incretin responsiveness. Furthermore, multi-agonist peptides combining xenin with other gastrointestinal hormones show synergistic potential in preclinical studies, concurrently augmenting insulin secretion and reducing energy intake, though their clinical relevance remains to be validated in human trials. Despite promising preclinical outcomes, challenges persist in translating xenin-based therapies to clinical practice, including incomplete mechanistic insights into receptor cross-talk and species-specific variations in gastrointestinal responses. This review uniquely integrates the preclinical landscape of xenin biology, peptide-engineering principles, and emerging multi-agonist design, identifying knowledge gaps critical for future translation. We conclude that xenin-based therapeutics are a promising yet early-stage strategy whose efficacy and safety in human metabolic diseases remain to be established through rigorous pharmacokinetic profiling and phased clinical trials.

Spindle Pole Body Component 25 (SPC25), a critical component of the NDC80 kinetochore complex, plays an essential role in maintaining chromosomal stability during mitosis. Recent studies have revealed its aberrant expression in various cancers, highlighting its potential as both a diagnostic biomarker and a therapeutic target. This review provides a comprehensive analysis of the molecular mechanisms underlying SPC25’s involvement in tumorigenesis, including its regulation of cell cycle progression and interaction with key oncogenic pathways. Furthermore, we discuss its prognostic significance across different cancer types and its potential impact on therapy resistance. The emerging evidence underscores SPC25’s multifaceted role in cancer biology, offering novel insights into its clinical applications. We conclude by exploring future research directions, emphasizing the need for in-depth studies to unravel the precise molecular functions of SPC25 and its therapeutic potential in cancer treatment.

The study aimed to explore potential links between long-term digestive issues (specifically diarrhea and constipation) and body roundness index (BRI) in a representative U.S. population sample. This study adopted a design that is cross sectional, drawing on data from the NHANES, gathered from 2005 to 2010 with health information from a total of 11,235 individuals. Persistent bowel movement patterns were categorized based on the BSFS—Bristol Stool Form Scale, while stool types 1 and 2 were designated as indicators of long-term constipation and types 6 and 7 were identified as markers of persistent diarrhea. To assess the relationship between digestive health and the BRI, this study employed weighted logistic regression analysis. To capture and visualize the nuanced interplay between BRI and gastrointestinal patterns, we utilized advanced nonlinear regression methods, specifically restricted cubic spline (RCS) analyses. Additionally, the research compared the efficacy of various physical measurements—including BRI, WC, BMI (body roundness index, waist circumference, and body mass index, respectively)—to determine their respective diagnostic power for chronic diarrhea and constipation through comparative analysis of receiver operating characteristic (ROC) curves. After comprehensive adjustment in the final statistical model (Model 3), the BRI demonstrated the statistically significant associations with diarrhea and persistent constipation. RCS analysis further uncovered statistically significant nonlinear positive associations of BRI and with diarrhea (P = 0.005) and constipation (P = 0.037). Further stratified analyses revealed that the relationship between BRI and persistent diarrhea was particularly evident among individuals with diabetes. In contrast, the association between BRI and constipation was stronger in individuals under 60 years of age. ROC analysis indicated that BRI outperformed conventional anthropometric measures (AUC, area under the curve: 0.601). Specifically, BMI resulted in an AUC of 0.569, while WC produced an AUC of 0.572. However, the AUC value of BRI (0.537) was less effective than BMI (0.551) and WC (0.570) in diagnosing constipation. BRI is strongly associated with changes in the individual’s bowel habits, particularly in diagnosing chronic diarrhea. This study highlighted the potential significance of maintaining moderate BRI levels to improve bowel health and prevent diarrhea.

BACKGROUND:A literature review revealed that intraductal papillary mucinous neoplasm of the biliary tract (IPMN-B) cases with characteristic clinical, imaging, endoscopic, and pathological features are exceedingly rare. Herein, we present a case of typical IPMN-B with malignant transformation that required 4 years for a definitive diagnosis, to enhance the understanding of this disease entity. CASE SUMMARY:A 67-year-old male patient was referred to our hospital due to abdominal pain and jaundice. Four years before this admission, a cystic lesion and left hepatolithiasis were incidentally discovered. Laboratory tests revealed mild increases in serum white blood cell count, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase. Tumour marker levels were within normal limits. Imaging findings demonstrated an enlargement of the cystic tumour from 41 mm to 63 mm, along with the development of numerous enhancing papillary nodules within it, which showed hyperenhancement during the arterial phase. Duodenoscopy revealed an enlarged major duodenal papilla with a fish-mouth appearance and dilated orifice, exuding translucent jelly-like mucus. Endoscopic retrograde cholangiography demonstrated multiple cloudy, irregular filling defects within the dilated extrahepatic bile duct. Following the diagnosis of IPMN-B, left hepatectomy was performed. Postoperative histopathological examination and immunohistochemistry confirmed IPMN-B with high-grade intraepithelial neoplasia and associated invasive carcinoma. CONCLUSION:Heightened vigilance and recognition of IPMN-B are essential when "hepatic cysts" or "biliary stones" are incidentally detected.

BackgroundPancreatic cancer, a highly lethal malignancy with limited therapeutic options, necessitates the identification of novel prognostic biomarkers and therapeutic targets. The extracellular matrix protein vitronectin (VTN) has been implicated in tumor progression, but its specific role in pancreatic cancer progression and immunotherapy response remains unclear.MethodsThis study employed an integrative approach combining single-cell RNA sequencing, analysis of public databases, and functional assays. In vitro experiments assessed the impact of VTN knockdown and overexpression on pancreatic cancer cell proliferation, invasion, and migration. Mechanistic investigations explored associations between VTN expression and immune regulatory factors. A syngeneic mouse subcutaneous tumor model evaluated the therapeutic efficacy of VTN overexpression combined with anti-PD1 immunotherapy.ResultsVTN was significantly downregulated in pancreatic cancer tissues compared to normal tissues. Lower VTN levels correlated with poorer overall survival. VTN knockdown promoted pancreatic cancer cell proliferation, invasion, and migration in vitro, whereas VTN overexpression suppressed these phenotypes. VTN expression was linked to immune regulatory pathways. High VTN levels predicted improved survival in patients receiving anti-PD1/PD-L1 therapy. In a mouse model, VTN overexpression inhibited tumor growth and synergized with anti-PD1 therapy to enhance antitumor efficacy, suggesting combinatorial therapeutic potential.ConclusionsThis study identifies VTN as a dual-functional regulator in pancreatic cancer, acting as both a suppressor of tumor progression and a modulator of immunotherapy response. These findings position VTN as a prognostic biomarker and a therapeutic target to sensitize pancreatic tumors to anti-PD1-based immunotherapy, providing a potential strategy for overcoming treatment resistance in this aggressive malignancy.

OBJECTIVE:This study aimed to explore the function of TNF receptor superfamily member 9 (TNFRSF9) in pancreatic ductal adenocarcinoma (PDA) by investigating its expression levels and functional implications in PDA cells. MATERIALS AND METHODS:TNFRSF9 expression was evaluated in patients with PDA, and TNFRSF9 levels were manipulated in PDA cells to assess its effects on cell proliferation, migration, and apoptosis. The downstream target gene PAX6 was also examined. In vivo, studies in nude mice were performed to analyze the impact of TNFRSF9 overexpression on tumor growth. RESULTS:Analysis revealed decreased TNFRSF9 expression in PDA tissues. Ectopic TNFRSF9 expression in PDA cells suppressed cell proliferation and migration and induced apoptosis, while TNFRSF9 knockout showed opposing effects. PAX6 was identified as a downstream target of TNFRSF9. TNFRSF9 overexpression in nude mice led to reduced tumor growth. CONCLUSION:The study suggests that TNFRSF9 may hold promise as a therapeutic target in PDA management, given its potential to inhibit tumor growth and modulate cell behavior.

Hepatocellular carcinoma (HCC) represents a major global health challenge, characterized by its complex immune microenvironment that plays a pivotal role in tumor progression and therapeutic response. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of various biological processes, including gene expression and immune cell function. This review explores the multifaceted roles of lncRNAs in modulating the immune microenvironment of HCC. We discuss how lncRNAs influence the infiltration and activation of immune cells, shape cytokine profiles, and regulate immune checkpoint molecules, thereby affecting the tumor’s immunogenicity and response to immunotherapy. Furthermore, we highlight specific lncRNAs implicated in immune evasion mechanisms and their potential as biomarkers and therapeutic targets. By elucidating the intricate interplay between lncRNAs and the immune landscape in HCC, this review aims to provide insights into novel strategies for enhancing immunotherapeutic efficacy and improving patient outcomes.

Abstract Background Pancreatic cancer is known for its poor prognosis and resistance to conventional therapies, largely due to the presence of cancer stem cells (CSCs) and aggressive angiogenesis. Effectively targeting these CSCs and associated angiogenic pathways is crucial for effective treatment. This study leverages single-cell multi-omics to explore a novel therapeutic approach involving Chimeric Antigen Receptor (CAR) macrophages engineered to target the c-Met protein on pancreatic CSCs. Methods We employed single-cell RNA sequencing to analyze pancreatic cancer tissue, identifying c-Met as a key marker of CSCs. CAR macrophages were engineered using a lentiviral system to express a c-Met-specific receptor. The phagocytic efficiency of these CAR macrophages against pancreatic CSCs was assessed in vitro, along with their ability to inhibit angiogenesis. The in vivo efficacy of CAR macrophages was evaluated in a mouse model of pancreatic cancer. Results CAR macrophages demonstrated high specificity for c-Met + CSCs, significantly enhancing phagocytosis and reducing the secretion of angiogenic factors such as VEGFA, FGF2, and ANGPT. In vivo, these macrophages significantly suppressed tumor growth and angiogenesis, prolonging survival in pancreatic cancer-bearing mice. Conclusion CAR macrophages targeting c-Met represent a promising therapeutic strategy for pancreatic cancer, offering targeted elimination of CSCs and disruption of tumor angiogenesis. This study highlights the potential of single-cell multi-omics in guiding the development of precision immunotherapies.

BackgroundThe expression level of apolipoprotein E (APOE) in pancreatic ductal adenocarcinoma (PDAC) and its effect on the prognosis of PDAC patients are not clear. The effect of APOE on the immune status of patients with PDAC has not been elucidated.MethodsWe obtained pancreatic cancer data from the TCGA and GETx databases. Patients with PDAC who underwent pancreatic surgery at the Second Affiliated Hospital of Jiaxing University between 2012 and 2021 were included. Clinical pathological data were recorded, plasma APOE levels were measured, and tissue samples were collected. A tissue microarray was generated using the collected tissue samples. APOE and CD4 staining was performed to determine immunoreactive scores (IRSs). The expression of APOE in the plasma and tumour tissues of pancreatic cancer patients was analysed and compared. The correlations between plasma APOE levels, tissue APOE levels and clinicopathological characteristics were analysed. Survival prognosis was analysed using Kaplan-Meier survival analysis and Cox multivariate regression analysis. The correlations between APOE expression levels and immune biomarkers and immune cells were further analysed. Single-cell analysis of APOE distribution in various cells was performed on the TISCH website.ResultsAPOE was highly expressed in the tumour tissue of pancreatic cancer patients, and high plasma APOE levels were associated with poor prognosis. Females, patients with high-grade disease and patients with pancreatic head carcinoma had high plasma APOE levels. High APOE expression in tumour tissues was associated with good prognosis. Mononuclear macrophages in the pancreatic cancer microenvironment primarily expressed APOE. APOE levels positively correlated with immune biomarkers, such as CD8A, PDCD1, GZMA, CXCL10, and CXCL9, in the tumour microenvironment. APOE promoted CD4 + T cell or dendritic cell infiltration in the tumour microenvironment.ConclusionsAPOE may affect the occurrence and development of pancreatic cancer by regulating the infiltration of immune cells in the tumour microenvironment.

The interaction between the immune system and the tumor matrix has a huge impact on the progression and treatment of cancer. This paper summarizes and discusses the crosstalk between T cells and cancer-associated fibroblasts (CAFs). CAFs can also produce inhibitors that counteract the function of T cells and promote tumor immune escape, while T cells can also engage in complex two-way interactions with CAFs through direct cell contact, the exchange of soluble factors such as cytokines, and the remodeling of the extracellular matrix. Precise targeted intervention can effectively reverse tumor-promoting crosstalk between T cells and CAFs, improve anti-tumor immune response, and provide a new perspective for cancer treatment. Therefore, it is important to deeply understand the mechanism of crosstalk between T cells and CAFs. This review aims to outline the underlying mechanisms of these interactions and discuss potential therapeutic strategies that may become fundamental tools in the treatment of cancer, especially hard-to-cure cancers.

Clear cell renal cell carcinoma (ccRCC) is a common kidney cancer with subtle early symptoms, high recurrence rates, and low sensitivity to traditional treatments like radiotherapy and chemotherapy. Identifying novel therapeutic targets is critical. The expression level of adenylate kinases 7 (AK7) in ccRCC was examined by the TCGAportal and UALCAN databases. The effect of AK7 on proliferation, invasion and migration of ccRCC cell lines was evaluated by cell assay. The correlation between AK7 expression and prognosis, as well as its direct relationship with immunotherapy efficacy, was analyzed using CANCERTOOL and Kaplan-Meier plotter data. Moreover, the TISIDB database was used to study the relationship between AK7 and immune markers. The effect of overexpressed AK7 combined with PD1 monoclonal antibody on ccRCC was evaluated in animal experiments. The results showed that low level of AK7 expression was observed in ccRCC tissues. The expression of AK7 can regulate the proliferation, invasion, and migration of human ccRCC cell lines. The level of AK7 expression was associated with OS of ccRCC patients. This was potentially due to the negative connection between AK7 expression and CD8+ T cell depletion, indicating that immunotherapy might be less effective in individuals with low AK7 expression. Conversely, augmenting AK7 demonstrated an enhanced effectiveness of anti-PD1 therapy. The findings of our research strongly indicated that AK7 could serve as both a prognostic indicator and therapeutic target for patients with ccRCC. Moreover, the overexpression of AK7 combined with anti-PD1 held promising potential as a therapeutic approach for treating ccRCC.

Introduction:Pancreatic carcinoma (PC) is a highly malignant digestive tumor. Nanotechnology-based minimally invasive techniques have been proposed to provide a new opportunity for PC treatment. Methods:A minimally invasive nanoplatform (named HA/DOX-AuNRs) is fabricated by HA modifying and DOX loading Au nanorings (AuNR). Because of their complicated geometric structure and tunable localized surface plasmon resonance peak in the second near-infrared laser window (NIR-II window), HA/DOX-AuNRs exhibit fluorescence/photoacoustic and photothermal properties, dual-responsive DOX release, and tumor-targeting ability. HA/DOX-AuNRs are expected to improve the tumor therapeutic efficiency and reduce undesirable side effects through fluorescence/photoacoustic dual-imaging guided targeted synergetic photothermal chemotherapy under NIR-II irradiation. Results:The morphological and physicochemical properties of HA/DOX-AuNRs are well-examined at first. The cytotoxicity, cellular uptake, and in vitro therapeutic effect of fluorescence/photoacoustic dual-imaging guided targeted synergetic photothermal chemotherapy are evaluated in Panc-1 cells. The in vivo biodistribution, anticancer effects, and systemic toxicity are investigated using PC xenograft models. Discussion:HA/DOX-AuNRs significantly improve the therapeutic efficacy in a dual-responsive and dual-imaging guided targeted synergy.

BACKGROUND Neuroendocrine carcinoma (NEC) of the extrahepatic bile duct is very rare, and the treatment and prognosis are unclear. Herein, we report the case of a middle-aged female with primary large cell NEC (LCNEC) of the common hepatic duct combined with distal cholangiocarcinoma (dCCA). Additionally, after a review of the relevant literature, we summarize and compare mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) and pure NEC to provide a reference for selecting the appropriate treatment and predicting the prognosis of this rare disease. CASE SUMMARY A 62-year-old female presented to the hospital due to recurrent abdominal pain for 2 months. Physical examination showed mild tenderness in the upper abdomen and a positive Courvoisier sign. Blood tests showed elevated liver transaminase and carbohydrate antigen 199 levels. Imaging examination revealed a 1-cm tumour in the middle and lower segments of the common bile duct. Pancreaticoduodenectomy + lymph node dissection was performed, and hepatic duct tumours were unexpectedly found during surgery. Pathology suggested poorly differentiated LCNEC (approximately 0.5 cm × 0.5 cm × 0.4 cm), Ki-67 (50%), synaptophysin+, and chromogranin A+. dCCA pathology suggested moderately differentiated adenocarcinoma. The patient eventually developed lymph node metastasis in the liver, bone, peritoneum, and abdominal cavity and died 24 months after surgery. Gene sequencing methods were used to compare gene mutations in the two primary bile duct tumours. CONCLUSION The prognosis of MiNEN and pure NEC alone is different, and the selection of treatment options needs to be differentiated.

The advent of PD1/PD-L1 inhibitors has significantly transformed the therapeutic landscape for clear cell renal cell carcinoma (ccRCC). This review provides an in-depth analysis of the biological functions and regulatory mechanisms of PD1 and PD-L1 in ccRCC, emphasizing their role in tumor immune evasion. We comprehensively evaluate the clinical efficacy and safety profiles of PD1/PD-L1 inhibitors, such as Nivolumab and Pembrolizumab, through a critical examination of recent clinical trial data. Furthermore, we discuss the challenges posed by resistance mechanisms to these therapies and potential strategies to overcome them. We also explores the synergistic potential of combination therapies, integrating PD1/PD-L1 inhibitors with other immunotherapies, targeted therapies, and conventional modalities such as chemotherapy and radiotherapy. In addition, we examine emerging predictive biomarkers for response to PD1/PD-L1 blockade and biomarkers indicative of resistance, providing a foundation for personalized therapeutic approaches. Finally, we outline future research directions, highlighting the need for novel therapeutic strategies, deeper mechanistic insights, and the development of individualized treatment regimens. Our work summarizes the latest knowledge and progress in this field, aiming to provide a valuable reference for improving clinical efficacy and guiding future research on the application of PD1/PD-L1 inhibitors in ccRCC.

Cholangiocarcinoma (CCA), a rare yet notably aggressive cancer, has experienced a surge in incidence in recent years. Presently, surgical resection remains the most effective curative strategy for CCA. Nevertheless, a majority of patients with CCA are ineligible for surgical removal at the time of diagnosis. For advanced stages of CCA, the combination of gemcitabine and cisplatin is established as the standard chemotherapy regimen. Despite this, treatment efficacy is often hindered by the development of resistance. In recent times, immune checkpoint inhibitors, particularly those that block programmed death 1 and its ligand (PD1/PD-L1), have emerged as promising strategies against a variety of cancers and are being increasingly integrated into the therapeutic landscape of CCA. A growing body of research supports that the use of PD1/PD-L1 monoclonal antibodies in conjunction with chemotherapy may significantly improve patient outcomes. This article seeks to meticulously review the latest studies on PD1/PD-L1 involvement in CCA, delving into their expression profiles, prognostic significance, contribution to oncogenic processes, and their potential clinical utility.

Cholangiocarcinoma (CCA), a rare yet notably aggressive cancer, has experienced a surge in incidence in recent years. Presently, surgical resection remains the most effective curative strategy for CCA. Nevertheless, a majority of patients with CCA are ineligible for surgical removal at the time of diagnosis. For advanced stages of CCA, the combination of gemcitabine and cisplatin is established as the standard chemotherapy regimen. Despite this, treatment efficacy is often hindered by the development of resistance. In recent times, immune checkpoint inhibitors, particularly those that block programmed death 1 and its ligand (PD1/PD-L1), have emerged as promising strategies against a variety of cancers and are being increasingly integrated into the therapeutic landscape of CCA. A growing body of research supports that the use of PD1/PD-L1 monoclonal antibodies in conjunction with chemotherapy may significantly improve patient outcomes. This article seeks to meticulously review the latest studies on PD1/PD-L1 involvement in CCA, delving into their expression profiles, prognostic significance, contribution to oncogenic processes, and their potential clinical utility.

Adenoid cystic carcinoma (ACC) is a malignant tumor that originates from exocrine gland epithelial cells. We profiled the transcriptomes of 49,948 cells from paracarcinoma and carcinoma tissues of three patients using single-cell RNA sequencing. Three main types of the epithelial cells were identified into myoepithelial-like cells, intercalated duct-like cells, and duct-like cells by marker genes. And part of intercalated duct-like cells with special copy number variations which altered with MYB family gene and EN1 transcriptomes were identified as premalignant cells. Developmental pseudo-time analysis showed that the premalignant cells eventually transformed into malignant cells. Furthermore, MYB and MYBL1 were found to belong to two different gene modules and were expressed in a mutually exclusive manner. The two gene modules drove ACC progression into different directions. Our findings provide novel evidence to explain the high recurrence rate of ACC and its characteristic biological behavior.