The multilayered intestinal barrier restricts transmucosal transport of therapeutic macromolecules, limiting effective treatment of inflammatory bowel disease (IBD). A noninvasive physical strategy capable of simultaneously enhancing drug delivery and restoring epithelial barrier integrity remains an unmet therapeutic challenge. Here, we developed a surface acoustic wave-integrated gastrointestinal device (SAW-GID), an endoluminal acoustofluidic platform that enables spatiotemporally programmable drug delivery and coordinated barrier repair. SAW facilitates cross-scale drug penetration by synergizing cavitation-free acoustic streaming (generating reversible sonopores at ~81 Pa) with acoustic radiation force-mediated “micro-massage”, resulting in up to a 13-fold enhancement of macromolecular delivery in intestinal tissue. TEER and Caco-2 monolayer models demonstrated that SAW induces a rapid, self-resolving (~15 min) drug delivery window via, Ca2+/cAMP-driven adherens and tight junction remodeling. In vivo, SAW-GID safely enhances barrier protein expression (ZO-1, occludin, MUC-2) and, in DSS-induced colitis, significantly improves mucosal integrity both alone and in combination with TNF-α siRNA. Mechanistically, SAW-GID modulates macrophage polarization toward an anti-inflammatory M2 phenotype and suppresses pro-inflammatory signaling pathways (TNF, IL-17, TLR), as confirmed by transcriptomic analysis. Moreover, SAW-GID restores microbial homeostasis, increasing beneficial taxa such as Lactobacillus, Ruminococcaceae UCG-014 and Coprococcus_1 while reducing pathogenic Escherichia-Shigella. Collectively, this work establishes a scalable and clinically translatable acoustofluidic platform that unifies targeted drug delivery with multi-layered barrier repair, offering a new mechanistically grounded therapeutic strategy for IBD.

‘Liver injury-liver fibrosis/cirrhosis-liver cancer’ is the key evolution pathway of hepatocellular carcinoma (HCC), chronic inflammation serving as a major driving force in this process. However, the regulatory mechanisms underlying this process require further clarification. Here, the carcinogen-induced liver injury, liver fibrosis, and HCC models were investigated in the wild-type and STK39-knockout mice. Mass spectrometry analysis and immunoprecipitation assays were used to identify the interaction factors of STK39. QPCR, ELISA, and immunofluorescence were applied for the expression of inflammatory factors. In this study, we report that STK39 is gradually upregulated during the evolution of HCC (liver injury-liver fibrosis-liver cancer). Consequently, overexpression of STK39 further encouraged the evolution of HCC by facilitating a macrophage inflammatory response, as demonstrated in carcinogen-induced liver injury, liver fibrosis, and HCC models. Pharmacological inhibition of STK39 significantly slows the progression of HCC; however, this effect was considerably diminished after macrophage clearance. Mechanistically, mass spectrometry analysis and immunoprecipitation assays identified that STK39 interacted with PKR and promoted the activation of the PKR/NF-κB axis. Which, in turn, enhanced the macrophage inflammatory response and accelerated the evolution of HCC. The inflammatory factor TNF-α further induces the expression of STK39, suggesting a positive feedback regulation process exists. More notably, STK39 inhibition improves the efficacy of sorafenib and anti-PD1 therapy. In conclusions, our study reveals that STK39 holds significant potential for the early diagnosis and treatment of HCC.

Kirsten rat sarcoma (KRAS)-mutant colorectal cancer (CRC) is characterized by aggressive metastatic progression and profound therapeutic resistance. While direct inhibitors have emerged recently, their clinical application is often limited by rapid adaptive resistance, highlighting the urgent need to explore new therapeutic targets. Here, we identify O6-methylguanine-DNA methyltransferase (MGMT), a classical DNA repair enzyme, as a novel epigenetic facilitator of metastasis in KRAS-mutant CRC. Through integrated analyses of clinical cohorts and orthotopic metastasis models, we found that MGMT is upregulated in KRAS-mutant tumors and correlates with liver metastasis. Functionally, MGMT promotes epithelial-mesenchymal transition (EMT) and enhances metastatic capacity in vivo and in vitro. Mechanistically, we unveil a non-canonical function of MGMT in CRC: it interacts with histone H3 and reduces repressive H3K9me3 marks at the promoter of the epithelial-mesenchymal transition master regulator TWIST1, thereby activating its transcription. Importantly, we demonstrate that targeting MGMT sensitizes KRAS-mutant colorectal cancer to anti-EGFR therapy in preclinical models, providing a novel combinatorial strategy for this recalcitrant cancer subtype. Our study redefines MGMT as a multifaceted chromatin-modifying protein and establishes it as a promising therapeutic vulnerability to bypass resistance in KRAS-mutant CRC.

Background:Robotic total gastrectomy (RTG) has been proposed as a promising alternative to laparoscopic total gastrectomy (LTG) for advanced middle-upper gastric cancer (AMUGC) due to its potential to overcome anatomical challenges. However, the comparative evidence regarding both safety and long-term oncologic efficacy remains limited. Methods:This retrospective cohort study included 1099 patients with AMUGC who underwent RTG/LTG at eight high-volume centers in China between 2015 and 2019. Propensity score matching (PSM = 1:1) was used to balance clinicopathological characteristics between the two groups. The primary outcome was 3-year disease-free survival (DFS); secondary outcomes included 3-year overall survival (OS), 3-year cumulative incidence of recurrence (CIR), recurrence patterns, and operative outcomes. Results:In the PSM cohort, 229 patients were included in each group. RTG demonstrated lower overall postoperative complications (16.2% vs. 27.1%, P < 0.05), medical complications (6.6% vs. 17.0%, P < 0.05), and pneumonia rates (6.6% vs. 16.2%, P < 0.05). No differences were observed in 3-year DFS (73.7% vs. 68.1%, P = 0.230), 3-year OS (76.8% vs. 72.4%, P = 0.326), CIR (24.4% vs. 26.8%, P = 0.580), and recurrence patterns. In stage III, 3-year DFS was higher in the RTG group (67.4% vs. 54.5%, P = 0.047), but no significant differences were found in 3-year OS or CIR (all P > 0.05). Multivariate analysis confirmed that the surgical method was not significantly associated with 3-year DFS [hazard ratio (HR), 0.767; 95% confidence interval (CI), 0.542-1.086; P = 0.135] or 3-year OS (HR, 0.774; 95% CI, 0.534-1.122; P = 0.177). Conclusions:For AMUGC patients not receiving neoadjuvant chemotherapy, RTG demonstrated potential advantages in certain operative outcomes and non-inferior 3-year oncological outcomes compared with LTG. Prospective trials are needed to validate these findings.

Robot surgery is an important trend in contemporary colorectal cancer surgical treatment. The Robotic Surgery Group, Colorectal Cancer Committee of Chinese Medical Doctor Association organized experts in relevant fields across the country to update and revise the application standards of robotic colorectal cancer surgery based on the Expert consensus on robotic surgery for colorectal cancer (2015 edition) and the revised version in 2020, in accordance with the development of robotic surgery concepts, technologies, and equipment in recent years, in order to promote the application and promotion of robotic surgery.

BackgroundThe rising incidence of rectal cancer (RC) in elderly patients contrasts with the scarcity of robust evidence comparing robotic-assisted and laparoscopic resection in this population. This study evaluated clinical outcomes and quality-of-life (QoL) metrics between these approaches in elderly patients with mid-low RC.MethodsConsecutive patients aged 70 years or older with mid-low RC who underwent minimally invasive resection at two tertiary centers from January 2017 to December 2024 were categorized into robotic (n=211) and laparoscopic (n=812) cohorts. Outcomes were analyzed using inverse probability of treatment weighting (IPTW) based on propensity scores.ResultsAfter IPTW, the effective sample comprised 2036 patients (1012 robotic group, 1024 laparoscopic group) with balanced clinicopathological characteristics. After matching, the pure operation time was comparable between groups (P>0.05), but the robotic approach achieved superior intraoperative outcomes, with significantly reduced estimated blood loss and lower incidence of intraoperative complications (all P < 0.05). Postoperatively, the cohort undergoing robotic-assisted procedures exhibited significantly lower rates of both overall complications and specific incidents of urinary retention. Longitudinal QoL assessment revealed sustained advantages in functional recovery, with the robotic cohort showing significantly better preserved urinary function, defecatory function, and male sexual function throughout the 12-month follow-up period (all P < 0.05). For patients with T4 stage tumors, the robotic approach demonstrated superior cancer-specific survival compared to laparoscopy, a benefit that was maintained after IPTW.ConclusionsRobotic-assisted surgery is a safe and feasible alternative for elderly patients with mid-low RC, offering reduced perioperative complications, superior functional preservation, and potential CSS benefits in T4 disease.

Background Certain gut bacteria are associated with improved responses to immunotherapy.Objective We aim to identify bacteria that inhibit colorectal cancer (CRC) progression and enhance immunotherapy efficacy.Design The abundance of bacteria in CRC patients was evaluated in our in-house cohorts and validated in published datasets. The effect of candidate bacterium with anti-PD-1 therapy was determined in two syngeneic mouse models of MC38 (microsatellite instability-high) and CT26 (microsatellite stable, MSS), transgenic Apcmin/+ mice and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC tumourigenesis model. Immune landscape changes were identified by multicolour flow cytometry and immunohistochemistry staining. Metabolomic profiling was performed on stool, serum and tumour tissues.Results Bifidobacterium catenulatum was significantly depleted in stool samples of 110 CRC patients compared with 112 healthy controls, which was further validated in 3 published metagenomic datasets comprising 198 CRC patients and 176 normal subjects. Oral administration of B. catenulatum inhibited tumour growths in multiple CRC models including MC38 and CT26 syngeneic models, Apcmin/+ mice and AOM/DSS-induced CRC. Notably, B. catenulatum synergised with anti-PD-1 therapy through enhancing intratumoural CD8+ T cell infiltration in MSS CRC models of Apcmin/+ mice and CT26 allografts. B. catenulatum-derived acetate was identified as the functional metabolite. Mechanistically, acetate directly bound to MCT-4 in CD8+ T cells and activated mitogen-activated protein kinase signalling. Pharmacological and genetic MCT4 ablation abolished acetate-mediated CD8+ T cell activation in vitro.Conclusion B. catenulatum suppresses colorectal tumourigenesis through generating acetate, which also improves anti-PD-1 efficacy through activating CD8+ T cells in MSS CRC. B. catenulatum is a potential adjuvant to improve immunotherapy against CRC.

The malignant transition of colorectal cancer (CRC) is caused by the combined action of epigenetic dysregulation and genomic instability. It is well known that EZH2-directed H3K27me3 modification is one of the main contributors to tumorigenesis; however, how it affects the DNA mismatch repair (MMR) system and the genesis of extrachromosomal circular DNA (eccDNA) remains unknown. Here, we demonstrate that EZH2 epigenetically represses critical MMR genes, which results in genomic instability and abnormal eccDNA accumulation, ultimately accelerating CRC progression. On the molecular level, the H3K27me3 mark catalyzed by EZH2 is the main cause of the downregulation of MMR genes, which affects the stability of the genome and leads to an increase in eccDNA that makes the tumor more aggressive. Our study reveals an unprecedented role of EZH2 in controlling chromosomal instability and eccDNA production through the MMR pathway and offers a conceptual framework for the development of CRC-targeted epigenetic therapies.

Cullin7 (CUL7) mediates cancer progression across multiple cancer types through its regulatory role in protein ubiquitination. However, the biological function and molecular mechanisms underlying CUL7 in colon cancer remain poorly defined. Here, we demonstrate that high CUL7 expression correlates with poor prognosis in patients. Ablation of CUL7 inhibited cell proliferation and migration in colon cancer cells, whereas CUL7 overexpression exhibited oncogenic properties. Moreover, Cul7-deplete mice exhibit a lower level of tumor growth. Mechanistically, CUL7 interacts with Kelch-like ECH-associated protein 1 (KEAP1) and catalyzes K29- and K48-linked polyubiquitination to promote its proteasomal degradation, which is crucial for NRF2 signaling. This leads to the decline of reactive oxygen species (ROS) and promotion of cancer growth. Importantly, the C-terminus of CUL7 is a crucial for governing KEAP1 stability and orchestrating antioxidant defense and cell growth. Clinical analysis identifies an inverse correlation between CUL7 and KEAP1 expression, and a positive correlation between CUL7 and NRF2 levels in human colon cancer. Our findings indicate that CUL7 mediates NRF2 signaling through promoting the KEAP1 ubiquitination, a mechanism that is integral to colon cancer progression. Collectively, these results establish CUL7 as a potential therapeutic target for colon cancer.

Irinotecan (CPT-11), a first-line chemotherapeutic agent for colorectal cancer, faces challenges like tumor drug resistance and severe toxicities such as neutropenia and diarrhea. Current nanocarriers for CPT-11 have limitations in achieving high drug loading and stimuli-responsive drug release. In this study, we developed a novel nanosystem (ICP@PDA-PP@HA NPs) by first coordinating CPT-11 and curcumin (Cur) with Fe3+ to form infinite coordination polymer nanoparticles (CPT11-Fe(III)-Cur ICPs), which were subsequently surface-modified with polydopamine (PDA) to yield ICP@PDA NPs. These NPs were then encapsulated in micelles composed of aldehyde-modified poly(ethylene glycol) (PEG) and poly(ethyleneimine) (PEI), followed by further modification with hyaluronic acid. The resulting nanosystem achieves efficient tumor targeting and ultra-sensitive pH-responsive drug release. CPT-11 induces immunogenic cell death (ICD) in tumor cells, while Cur enhances CPT-11 intracellular accumulation and reduces resistance. PDA-mediated photothermal therapy, when combined with dual-drug chemotherapy, synergistically induces ICD through non-repetitive multiple pathways, thereby enhancing the antitumor immune response. In vivo experiments showed that low-dose ICP@PDA-PP@HA NPs achieved a tumor inhibition rate of 95.8% after 21 days, and when combined with anti-PD-L1, the tumor inhibition rate reached 100% with no recurrence within 90 days.

BACKGROUND:Colorectal cancer (CRC) is a common malignant tumor of the digestive tract with high morbidity and mortality. Previous studies have shown that circular RNA (circRNA) circRBM33 (also known as hsa_circRNA_104532) was implicated in the pathogenesis of various human cancers. This study aims to investigate the potential function and working mechanism of circRBM33 in CRC. METHODS:circRBM33, microRNA-512-5p (miR-512-5p), and solute carrier 1 family member 5 (SLC1A5) levels were detected using real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferative ability, apoptosis, and migration were analyzed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, and wound healing assay. C-myc, CyclinD1, and SLC1A5 protein levels were measured using Western blot. The glycolysis levels were evaluated using specific kits. The biological role of circRBM33 on CRC tumor growth was assessed using the xenograft tumor model in vivo. After circular RNA Interactome and Targetscan prediction, the binding between miR-512-5p and circRBM33 or SLC1A5 was verified using a dual-luciferase reporter assay. RESULTS:CircRBM33 and SLC1A5 were increased, and miR-512-5p was decreased in CRC tissues and cells. From a functional perspective, circRBM33 knockdown could hinder cell proliferation, migration, glutamine metabolism, and boost apoptosis in CRC cells. Also, circRBM33 silencing could suppress the cell growth of CRC in vivo. The mechanical analysis suggested that circRBM33 could increase SLC1A5 expression via sponging miR-512-5p. CONCLUSION:CircRBM33 boosted CRC development partly by regulating the miR-512-5p/SLC1A5 axis, providing a promising therapeutic target for CRC therapy.

Objective:Robotic gastrectomy (RG) is increasingly used in the treatment of gastric cancer. However, studies on patients with clinical serosa-invasive (cT4a) gastric cancer remain scarce. This study aimed to compare the short- and long-term outcomes of RG and laparoscopic gastrectomy (LG) in the treatment of stage cT4a gastric cancer. Methods:A retrospective analysis was conducted on the clinical data of patients with stage cT4a gastric cancer diagnosed and treated at eight high-volume tertiary teaching hospitals in China from 2016 to 2019. Propensity score matching (PSM) analysis and inverse probability of treatment weighting (IPTW) analysis was used to adjust for the imbalance in baseline characteristics. The primary research endpoint was the 3-year overall survival (OS) and disease-free survival (DFS). The secondary research endpoint was intraoperative outcomes and postoperative complications. Results:After IPTW and PSM adjustments, baseline characteristics between the RG and LG groups were comparable [standardized mean difference (SMD) <0.10]. Post-PSM analysis revealed that the RG group exhibited longer operative time (P<0.001), lower postoperative complication rates (P<0.001), shorter postoperative hospital stays (P=0.037), and earlier initiation of adjuvant chemotherapy (P=0.041) compared with the LG group. Survival analysis demonstrated comparable 3-year OS (P=0.110) and DFS (P=0.088) in the PSM cohort, whereas the IPTW cohort showed superior OS (P=0.030) and DFS (P=0.046) for RG. No significant differences were observed in overall recurrence rates or recurrence sites between groups. Conclusions:For patients with stage cT4a gastric cancer, compared with the LG group, the RG group had shorter postoperative hospital stay, lower incidence of postoperative complications, earlier postoperative adjuvant chemotherapy, and no worse long-term efficacy.

BACKGROUND:While robotic gastrectomy (RG) is increasingly used in gastric cancer surgery, its potential advantages over laparoscopic gastrectomy (LG) in intraoperative technical complexity (ITC) cases remain debated. METHODS:This retrospective cohort study included 3534 patients with gastric cancer who underwent radical gastrectomy at eight high-volume hospitals. ITC was defined by any of the following criteria: operative time exceeding the third quartile, intraoperative estimated blood loss ≥400 mL, or conversion to open surgery. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were conducted to compare short- and long-term outcomes. RESULTS:Patients with ITC comprised 25.9% (916/3534) of the cohort (RG: 260, LG: 656). After baseline adjustment, RG and LG groups were comparable in both PSM and IPTW cohorts. RG showed lower overall postoperative complications (11.5% vs. 20.1%, P = 0.003), particularly pneumonia (2.3% vs. 11.0%, P < 0.001) and shorter postoperative hospital stay (9.33 ± 4.41 vs. 10.77 ± 5.91 days, P < 0.001) compared to LG. These differences remained significant after PSM and IPTW analysis. The 3-year overall survival (83% vs. 78.8%, P = 0.15), disease-free survival (81.9% vs. 76.2%, P = 0.073), and cumulative recurrence risk (16.9% vs. 20%, P = 0.26) were comparable between RG and LG groups, consistent after PSM and IPTW. Multivariate analysis indicated that the surgical approach was not an independent factor influencing technical complexity. CONCLUSIONS:For patients with ITC, RG demonstrated superior short-term and comparable long-term outcomes than LG.

In the original publication [...].

Extrachromosomal circular DNA (eccDNA) has potential in tumor diagnosis, particularly for improving diagnostic accuracy and early cancer detection; however, many challenges remain in its application to clinical practice. We conducted a Circle‐Seq analysis on clinical samples at different stages of colorectal cancer progression to examine the dynamic changes of eccDNA during the progression of colorectal cancer. We used breakpoint-specific PCR to verify candidate eccDNAs identified by Circle‐Seq. The results were further validated using the AOM/DSS-induced colorectal cancer model. There was an increase in the abundance of eccDNA with the progression of colorectal cancer. The genes associated with these eccDNA molecules were primarily related to signaling pathways involved in tumor development and metastasis. Our analysis also revealed that eccDNA abundance positively correlates with gene expression, and eccDNA derived from specific genes has potential value for the early diagnosis of tumors. This study revealed a connection between eccDNA and colorectal cancer progression and highlights the clinical potential of eccDNA for the early diagnosis of colorectal cancer.

Robotic and endoscopic cooperative surgery (RECS) is an emerging and promising therapeutic approach for treating gastric submucosal tumors (GSMTs). However, the efficacy of RECS has not been well established, and its high medical costs significantly limit its application. This nested cohort study examined patients with GSMTs managed with different surgical techniques. A total of 314 consecutive patients were enrolled in this study, including 61 patients treated with RECS, 196 patients treated laparoscopically, and 57 patients treated with open surgery. To mitigate confounding bias, 1:1:1 propensity score matching (PSM) was utilized. The perioperative outcomes, postoperative gastrointestinal symptoms, long-term outcomes, and cost-effectiveness among the three groups were compared. After PSM, 51 patients were included in each group. Compared with the laparoscopic and open surgical groups, the RECS group presented significantly lower intraoperative bleeding volumes, times to first flatus, times to liquid intake, and postoperative hospital stay. The severity of gastrointestinal symptoms in the RECS group was notably better than that in the laparoscopic and open groups 3, 6, and 12 months postsurgery. Regarding long-term outcomes, there were no differences in overall or relapse-free survival among the three groups. The total hospitalization cost was significantly greater in the RECS group, primarily due to surgical cost differences. The incremental cost-effectiveness ratios per quality-adjusted life year for the RECS group relative to the laparoscopic and open groups were 18,244 and 56,914 Chinese yuan (CNY), respectively. Analysis of the cost-effectiveness acceptability curves indicated that across all willingness-to-pay thresholds, the probability that RECS was cost-effective exceeded 90

ABSTRACTTo improve the long‐term therapeutic efficacy of colorectal cancer, we propose a synergistic treatment strategy involving dual‐pathway, multistep induction of long‐term hyperimmunity combined with photothermal‐chemotherapy. To implement this strategy, infinite coordination polymer nanoparticles (SN38‐Mn(II)‐EGCG ICP NPs) were prepared by coordinating SN38, EGCG, and Mn2+. These nanoparticles were then coated with polydopamine (PDA) and grafted with folate‐PEG‐thiol (FA‐PEG‐SH) onto their surfaces, producing tumor‐targeting folate‐modified PDA infinite coordination polymer nanocomposites (ICP@FA‐PDA nanocomposites). These nanocomposites exhibit a particle size of 94.9 ± 1.6 nm with a high drug loading capacity (83.3% ± 1.5%), drug release under acidic conditions while maintaining stability in physiological environments. Furthermore, each component within the nanocomposites serves multiple functions. Notably, the incorporation of multiple components triggers a powerful antitumor immune effect and establishes enduring immune memory through a dual‐pathway and multistep approach, which is produced with the activation of the cGAS‐STING pathway and immunogenic cell death (ICD) by a four‐component multistep process. Under a low‐dose regimen, this approach induces dual‐pathway hyperimmunity effect and generates ultra‐long immunological memory, marked by a ninefold increase in CD8+ T cell infiltration, a fourfold increase in CD4+ T lymphocytes, a fourfold reduction in Treg cells, and a fivefold increase in memory T cells. The remarkable therapy efficacy is achieved by hyperimmunity effect combination of SN38 and EGCG chemotherapy and photothermal therapy. In vivo studies demonstrated that mice treated with ICP@FA‐PDA nanocomposites achieved complete eradication of cancer within 21 days, with no recurrence observed within 60 days. These nanocomposites hold significant promise and potential for future clinical translation.

The comparative efficacy of robotic (RG) and laparoscopic gastrectomy (LG) in patients with gastric cancer with a body mass index (BMI) ≥ 25 kg/m2 remains unclear. We compared the outcomes between RG and LG in this patient population. This multicenter cohort study included 695 patients with gastric cancer with BMI ≥ 25 kg/m2 who underwent RG (n = 220) or LG (n = 475) at eight high-volume teaching hospitals in China. To reduce intergroup differences, overlap weighting (OW) and inverse probability of treatment weighting (IPTW) were applied. The primary end-points were short-term outcomes, 3-year survival, and recurrence. After OW and IPTW adjustments, the two groups’ baseline characteristics were well-balanced. Intraoperative blood loss, major bleeding rates, number of perioperative transfusions, and incidence of medical complications were lower, while operative time and costs were greater in the RG than LG group (all P < 0.05). Postoperative pneumonia rates tended to be lower in the RG group. The 3-year disease-free survival (DFS) or overall survival (OS) were comparable between groups. Subgroup analyses revealed no statistically significant interactions between the surgical approach and DFS or OS across all variables (all interactions, P > 0.05). Recurrence rates and patterns were comparable between the groups (all P > 0.05). For patients with gastric cancer with BMI ≥ 25 kg/m2, RG offers superior short-term outcomes compared to LG, while demonstrating non-inferior 3-year oncological outcomes. RG is a safe and effective surgical approach for managing gastric cancer in patients with elevated BMI.