3620 Background: Immune checkpoint inhibitors in neoadjuvant setting have brought clinical benefits for patients with various tumors. This study aimed to evaluate the efficacy and safety of iparomlimab and tuvonralimab (QL1706), a bifunctional antibody targeting both PD-1 and CTLA-4, as neoadjuvant treatment in patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) colon cancer. Methods: In this single-arm phase 1b trial, previously untreated patients with resectable stage IIb-III MSI-H/dMMR colon cancer were recruited. Patients were administered neoadjuvant treatment of QL1706 at 5 mg/kg via intravenous infusion every three weeks for four cycles. Radical resection was scheduled between 4 and 6 weeks after last dose of neoadjuvant treatment. The primary endpoint was pathological complete response (pCR) rate. The efficacy analysis set included patients who were confirmed dMMR/MSI-H, received at least one dose of treatment, and had post-surgery pathological results. The safety analysis set included patients who received at least one dose of treatment. Results: As of data cut-off date on Oct 15, 2025, 43 patients were enrolled (median age: 56.0 years; males: 58.1%; ECOG PS 1: 55.8%; Lynch syndrome: 34.9%). Scheduled radical resection were performed in 34 patients. A total of 34 patients were included in the efficacy analysis set. The pCR rate was 88.2% (30/34, 95% confidence interval [CI]: 72.5%-96.7%). The major pathologic response rate was 91.2% (31/34, 95% CI: 76.3%-98.1%). In high-risk patients (T4 or N2), the pCR rate was 86.4% (19/22, 95% CI: 65.1%-97.1%). All patients (100%) received surgery had R0 resection. Median treatment exposure was 2.1 months (range, 0.0-3.9). Treatment-emergent adverse events (TEAEs) of grade ≥3 occurred in 12 patients (27.9%); two (4.7%) patients were treatment-related. Immune-related adverse events grade ≥3 occurred in two (4.7%) patients, including one grade 3 acute kidney injury and one grade 4 hypersensitivity, both of which recovered finally. Treatment-related serious adverse events occurred in three (7.0%) patients. No patient cancelled or delayed the surgery due to TEAE. No TEAE leading to death occurred. The incidence of grade ≥3 TEAE during the surgery phase was 11.8% (4/34). Conclusions: Neoadjuvant treatment of QL1706 showed promising pCR rate and manageable safety in patients with MSI-H/dMMR colon cancer. A phase 3 trial is ongoing to further confirm the efficacy and safety of QL1706 as neoadjuvant treatment in patients with resectable MSI-H/dMMR colon cancer. Clinical trial information: NCT06686576 .

Circulating tumor DNA (ctDNA) derived from blood samples can serve as a minimally invasive, real-time indicator of tumor burden and treatment response in metastatic colorectal cancer. This study evaluated the association between baseline ctDNA levels and changes in ctDNA during treatment with response and survival outcomes in the phase II ALTER-C-002 trial, which investigated first-line anlotinib combined with capecitabine and oxaliplatin in patients with rat sarcoma (RAS) and B-Raf proto-oncogene (BRAF) wild-type metastatic colorectal cancer. In this post-hoc biomarker analysis, plasma samples were collected at baseline, near the best radiologic response (C1), and at the timepoint closest to disease progression or last follow-up (C2). These samples were analyzed using a 90-gene next-generation sequencing (NGS) panel, with ctDNA abundance quantified as maximum somatic allele frequency (MSAF), where MSAF <0.001 indicated ctDNA negativity. Biomarker data were obtained for 26 patients, 25 of whom had measurements at all three timepoints. Notably, baseline MSAF was higher in patients with liver-only metastasis (p=0.017). MSAF decreased significantly at C1 compared to baseline (p<0.001) and increased at C2 relative to C1 in patients exhibiting progressive disease (PD) (p<0.001); additionally, higher MSAF at C1 was associated with subsequent PD at C2 (p=0.015). All patients who tested ctDNA-negative at C1 achieved an objective response, and ctDNA negativity at this timepoint correlated with longer progression-free survival (PFS) (p=0.012) and overall survival (OS) (p=0.006) compared to ctDNA-positive patients. Furthermore, KRAS/BRAF mutations detected in ctDNA were linked to shorter PFS and OS (all p<0.05). In conclusion, baseline ctDNA burden and early ctDNA clearance may function as prognostic and on-treatment biomarkers of therapeutic efficacy in metastatic colorectal cancer, warranting prospective validation.

Purpose We aim to develop an updated, parsimonious pathological TNM staging system with ideal hierarchical outcomes for non-metastatic colorectal cancer (CRC). Methods Available individual patient data from 161208 patients with non-metastatic CRC were collected from the SEER database (2010-2020, training dataset) and the Zhejiang Cancer Hospital (ZJCH) (2010-2024, validation dataset). The TNtdM framework was proposed by integrating the tumor deposit (TD) counts into N staging and reweighting T staging. Results TD was significantly associated with poor prognosis in patients with non-metastatic CRC (HR =1.39; P <0.001), and its count was found to negatively linearly correlated with cancer-specific survival (CSS) (TD1: 1-3, HR =1.31; TD2: ≥ 4, HR =1.77; P <0.001). The novel NTD staging system (NTD0-4), integrating N and TD categories, robustly stratified patients into five groups with monotonically declining 5-year CSS rates from 87.2% (NTD0) to 38.9% (NTD4) (P <0.001). By incorporating this NTD system and increasing the weighting of T staging, the TNtdM staging system, comprising 7 substages (stages IA, IB, IIA, IIB, IIIA, IIIB, and IIIC), was established and successfully resolved the survival paradox (e.g. the 5-years CSS rates: 79.6% in stage IIA, 70.5% in stage IIB, 57.6% in stage IIIA). The survival curves stratified by the TNtdM classification demonstrated excellent separation and stepwise deterioration of CSS with increased substages. Compared with the 8th edition AJCC TNM staging system, the TNtdM exhibited higher discrimination power and better goodness-of-fit. The above results were further external validated in the ZJCH cohort. Conclusions The TNtdM staging system provided superior risk stratification and more accurate prognostic information than the current AJCC staging, thereby supporting its implementation in guiding precise clinical decision-making for non-metastatic CRC.

The Tianhe Procedure is a functional sphincter-preserving surgical approach developed for patients with rectal cancer following radiotherapy. This technique involves proximal extended resection of the colon beyond the pelvic cavity, followed by anastomosis of the non-irradiated proximal colon to the distal rectum or anal canal. This strategy aims to reduce the incidence of anastomotic complications and postoperative bowel dysfunction. However, there is currently a lack of standardized practice guidelines for implementing the Tianhe Procedure in China. Therefore, the Chinese Radiation Intestinal Injury Research Group, the Colorectal Surgery Group of Surgery Branch of the Chinese Medical Association, the Anorectal Branch of Chinese Medical Doctor Association, the Colorectal Cancer Committee of the Chinese Medical Doctor Association, the Colorectal Cancer Committee of China Anti-cancer Association, and the Gastrointestinal Surgical Branch of Guangdong Medical Doctor Association have jointly convened a panel of national experts to discuss and establish this standardized surgical procedure. This standard, based on the latest evidence from literature, research advancements, and expert experience, focuses on key aspects of the Tianhe Procedure, including its precise definition, indications, critical procedural steps, postoperative complications, and functional rehabilitation strategies. It aims to promote standardized implementation and broader clinical adoption of this innovative surgical technique.

Fusobacterium nucleatum (F. nucleatum) is known as a common microbial factor involved in the development of colorectal cancer (CRC) and liver metastasis, with emerging evidence suggesting its potential impact on the tumor immune microenvironment. The precise identification and appropriate characterization of this microorganism, along with immune-related biomarkers, are essential for understanding disease development and facilitating better diagnostic and monitoring approaches. Nonetheless, conventional microbiological and immunological techniques are constrained as a result of low sensitivity, limited multiplexing capability, and insufficient integration with intricate datasets related to tumors. The present review aims to provide a comprehensive and method-focused perspective on innovative analytical strategies for the concurrent identification of F. nucleatum and analysis of immune microenvironment signatures in CRC and CRC liver metastasis (CRLM). Advances in various nucleic acid-based technologies, such as digital PCR, CRISPR-based diagnostics, and next-generation sequencing, are discussed for their ability to provide highly sensitive and specific microbial detection. Furthermore, mass spectrometry and multi-omics techniques, including proteomics, metabolomics, and microbiome profiling, are described for their potential to clarify host-microbe interactions within metastatic niches. Moreover, recent advancements in biosensors and microfluidic technologies are emphasized as promising tools for rapid and point-of-care analysis, while chemometric and machine learning strategies are critically evaluated for their role in integrating complex datasets and facilitating predictive modeling of microbiome-immune interactions. By addressing these technologies and significant challenges, such as analytical validation, standardization, and clinical implementation, this review highlights how next-generation analytical strategies are reshaping the detection and characterization of microbiome-driven immune modulation in CRC and CRLM, paving the way for new biomarker discovery and precision diagnostics.

92 Background: Microsatellite stable (MSS) locally advanced rectal cancer (LARC) is refractory to immune checkpoint inhibitors. Our prior Phase II trial demonstrated remarkable efficacy, suggesting short-course radiotherapy (SCRT) plus chemotherapy acts as a potent immunogenic primer for PD-L1 blockade (via subcutaneous envafolimab). We conducted this multicenter, randomized Phase III trial (PRECAM-R) to validate if this patient-centric strategy, combining SCRT, chemotherapy, and immunotherapy, improves outcomes versus standard care. Methods: Patients with resectable, stage II/III (cT3-4a/N+) MSS LARC were randomized (1:1) to the Experimental Group (SCRT 5×5 Gy, then only 2 cycles CAPEOX plus subcutaneous envafolimab) or Control Group (SCRT then CAPEOX). Total mesorectal excision (TME) was performed following neoadjuvant therapy. The primary endpoint was pCR (ypT0N0). Secondary endpoints included tumor regression grade (TRG), Neoadjuvant Rectal (NAR) score, and safety. This pre-specified interim analysis was triggered after 58 patients completed surgery. Results: Fifty-eight eligible eligible patients were randomized (n=29 per arm). Baseline characteristics were well-balanced; 77.6% had Stage III disease. The Experimental Group achieved a pCR rate of 44.8% (13/29), significantly tripling that of the Control Group (13.8% [4/29]; P = 0.0195). Major pathological response (TRG 0-1) rates were 72.4% vs. 51.7% (P = 0.176). The Experimental Group showed superior distribution of tumor downstaging based on NAR scores ( P = 0.036). Notably, early distant metastasis occurred in 13.8% (4/29) of patients in the Control Group (liver/lymph nodes) compared to 0% in the Experimental Group. The addition of envafolimab was well-tolerated, with Grade 3-4 adverse events comparable to the control arm (3.4% vs. 0%, P > 0.99). Crucially, this strategy did not compromise surgical safety, showing no increase in operative complexity or postoperative complications (10.3% vs 13.8%, P > 0.99). Conclusions: This regimen, featuring a patient-centric short-course backbone, shows promise in overcoming resistance to PD-L1 blockade in MSS LARC. This strategy yields high pCR rates and tumor regression with high compliance and a favorable safety profile. The early signal for systemic control positions this convenient regimen as a compelling option for organ preservation. Clinical trial information: NCT05752136 . Interim efficacy and safety outcomes. Endpoint Experimental (n=29) Control (n=29) P Value Primary Endpoint pCR (ypT0N0), No. (%) 13 (44.8) 4 (13.8) 0.0195 Secondary Endpoints MPR (TRG 0-1), No. (%) 21 (72.4) 15 (51.7) 0.176 Median NAR Score (IQR) 8.43 (0.94-8.43) 8.43 (6.66-14.98) 0.036 Distant Metastasis, No. (%) 0 (0) 4 (14.8) 0.112 Grade 3-4 Adverse Events, No. (%) 1 (3.4) 0 (0) 0.99 Postoperative Complications, No. (%) 3 (10.3) 4 (13.8) 0.99

Serum bile acids (BAs) emerge as risk factors for cancer, but their roles in colorectal cancer (CRC) remain unclear. We show that glycocholic acid (GCA), a primary BA, is elevated in the serum of CRC patients. In a mouse CRC model, GCA promotes tumor programmed death-ligand 1 (PD-L1) expression in tumors, suppressing CD8⁺ T cell-mediated antitumor immunity and facilitating tumor growth. Mechanistically, GCA inhibits the BA receptor farnesoid X receptor (FXR), a transcriptional repressor for SRY-box transcription factor 14 (SOX14). Loss of FXR repression upregulates SOX14-mediated expression of zinc finger DHHC-type palmitoyl transferase 9 (DHHC9), thereby reducing PD-L1 palmitoylation and stabilization. Silencing SOX14 or DHHC9, or activating FXR, synergizes with anti-PD-1 therapy, reducing tumor growth in GCA-treated mice. These findings uncover a mechanism that GCA remodels the tumor microenvironment to mediate CRC resistance to immunotherapy, highlighting therapeutic opportunities targeting the FXR-PD-L1 axis in CRC patients with elevated serum GCA.

BACKGROUND:In a bridging study of INTRIGUE, second-line ripretinib demonstrated comparable progression-free survival (PFS) and favorable safety versus sunitinib in Chinese patients with advanced gastrointestinal stromal tumor. Overall survival (OS) was highly immature at the time of primary analysis. This updated analysis assessed long-term OS of ripretinib versus sunitinib. METHODS:This phase 2, multicenter, randomized, open-label study in China enrolled patients with gastrointestinal stromal tumor previously treated with imatinib, randomized (1:1) to ripretinib 150 mg once daily by continuous dosing in 42-day cycles or sunitinib 50 mg once daily in 42-day cycles (four weeks on/two weeks off). The updated analysis assessed OS and PFS on third-line therapy in all-patient intention-to-treat and KIT exon 11-mutated intention-to-treat (Ex11 ITT) populations. RESULTS:Of 108 patients randomized, 54 received ripretinib and 54 sunitinib; 70 had a primary KIT exon 11 mutation (ripretinib, n = 35; sunitinib, n = 35; Ex11 ITT). By December 30, 2024, in all-patient intention-to-treat population, median OS was 43.3 months with ripretinib and 29.9 months with sunitinib (hazard ratio, 0.681; 95% CI, 0.411-1.126; nominal p = .134). In the Ex11 ITT population, median OS was 43.3 months with ripretinib and 28.6 months with sunitinib (hazard ratio, 0.552; 95% CI, 0.291-1.047; nominal p = .065). PFS on third-line therapy was comparable between treatment arms in both populations. CONCLUSIONS:After two additional years of follow-up, ripretinib showed a trend toward clinically meaningful OS benefit versus sunitinib in the Ex11 ITT population. Second-line ripretinib does not appear to affect third-line treatment efficacy.

Colorectal cancer (CRC) is a highly prevalent malignancy and a leading cause of cancer-related mortality globally, necessitating the exploration of innovative diagnostic and therapeutic strategies alongside conventional approaches such as surgery, chemotherapy, and radiotherapy which exhibit inherent limitations. This review systematically examines recent advancements in CRC research, particularly focusing on early diagnostic methodologies, novel surgical techniques, advancements in radiotherapy and chemotherapy, as well as the burgeoning fields of immunotherapy and targeted therapies. A comprehensive search of the PubMed database was conducted to collate key clinical studies published over the last three years in order to assess the current landscape of CRC management. The results emphasize the paramount importance of early diagnosis and innovative surgical strategies while highlighting significant progress in radiotherapy and chemotherapy, with immunotherapy and targeted treatments emerging as promising avenues. Notably, the increasing incidence of aggressive early-onset colorectal cancer (EO-CRC) reinforces the urgent need for effective screening and prevention frameworks, supplemented by interdisciplinary treatment teams that are crucial for optimal patient management. Enhanced pathological diagnosis is vital for informing adjuvant chemotherapy decisions, and ongoing advancements in surgical methods and systemic therapies are contributing to improved patient outcomes. Furthermore, the potential of personalized cancer therapy through targeted approaches presents an exciting frontier, though further investigation is essential to better delineate candidate identification for immunotherapy. Targeted sequencing panels could play a pivotal role in optimizing patient selection for these emerging therapies, thereby augmenting CRC treatment strategies in the future.

Lung metastasectomy has been considered the cornerstone of treatment of resectable colorectal cancer pulmonary oligometastases (CRCPOM). However, the role of chemotherapy in the neoadjuvant setting remains unclear. This study aimed to determine whether neoadjuvant therapy (NAT) could further improve survival outcomes of patients with resectable CRCPOM. We included all 253 consecutive patients at our center between 2010 and 2022. Propensity score matching (PSM) was performed to balance the baseline characteristics. The efficacy of NAT was evaluated using the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Disease-free survival (DFS) was the primary endpoint, which was estimated by the Kaplan–Meier method. Multivariate analyses were conducted using Cox proportional hazards regression to identify independent predictors. The cumulative 5- and 10-year DFS rates following lung metastasectomy were 48.3

Therapeutic strategies for peritoneal metastasis in solid tumors are urgently needed. Programming chimeric antigen receptor macrophages (CAR-Ms) in situ offers opportunities for an unmet demand. However, potential intracellular domains (ICDs) for CAR design and their antitumor mechanisms for macrophage empowerment remain to be explored systematically. By developing a macrophage-targeted mRNA lipid nanoparticle (mRNA-LNP) system, we evaluate 36 CAR formats in CAR-Ms. Tailored CAR-Ms with CD3ζ TLR4 ICDs elicit robust adaptive immune activation and significantly synergize with PD-1/L1 therapy. Single-cell RNA sequencing (scRNA-seq) reveals that CAR-Ms reshape the immunosuppressive tumor microenvironment (TME) and boost the TCF1+PD-1+ progenitor-exhausted CD8+ T cells (Tpex) population. Mechanistically, CAR-Ms maintain a proinflammatory phenotype and simultaneously upregulate MHC-I and PD-L1 by perturbing NF-κB pathways. Collectively, this approach enables intraperitoneal programming of tailored CAR-Ms and broadens understanding of both regulatory and feedback mechanisms for CAR-M therapies against solid tumors.

Current diagnostic modalities lack sufficient sensitivity for detecting omental metastasis (OM), often underestimating metastatic burden. Unlike traditional statistical model, machine learning (ML) model is designed to detect subtle variable interactions and model nonlinear patterns that traditional statistics overlook, enhancing the reliability of OM risk evaluation in clinical practice. The aim of the study was to build a ML model in preoperatively predicting OM in right-sided colon cancer (RCC) patients using a multicenter dataset. This retrospective multicenter study included 1798 RCC patients: 1206 from Zhejiang Cancer Hospital (training set n = 804, test set n = 402) and 592 from the Second Affiliated Hospital of Harbin Medical University (validation set). OM status, tumor location, preoperative CEA level, preoperative CA199 level, Grade, histology, tumor size and age of patients were recorded. Six ML models including extreme gradient boosting (XGB), artificial neural network (ANN), logistic regression (LR), random forest (RF), support vector machine (SVM) and decision tree (DT) were developed for the OM prediction in RCC. The area under the receiver operator characteristic (ROC) curve (AUC), accuracy, sensitivity, specificity, precision, F1 score and decision curve analysis (DCA) were analyzed for judging predictive performance. The OM rates in training set, test set and validation set were 10.4

BACKGROUND:Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusion partner distribution, and unique kinase domain distribution. METHODS:We conducted a multicenter study to comprehensively profile FGFR fusions in the largest Chinese pan-cancer cohort to date, comprising 118 FGFR fusions from 114 individuals. Both DNA- and RNA-based sequencing approaches were utilized to reveal novel and fundamental features of FGFR fusion. RESULTS:Our research reveals an incidence rate of 0.96% for FGFR rearrangements within this Chinese cohort, including a high incidence rate of FGFR fusions (40%) in parotid gland carcinoma. However, this is based on a small sample size of 5 tumors and should be interpreted cautiously pending validation in larger cohorts. We also uncovered distinct breakpoint distribution patterns across various FGFR rearrangements. For example, a primary breakpoint in intron17 of FGFR2 was predominant (21/22), while FGFR1/3 breakpoints displayed substantial diversity. For the first time, we identified "hot" breakpoints in FGFR1 intron17, exon18, and FGFR3's 3' untranslated region. These findings underline the importance of incorporating these regions in targeted sequencing to ensure comprehensive detection of FGFR1/3 fusions. Notably, we observed a predilection for intrachromosomal distribution in common FGFR1/2/3 fusions. In contrast, most novel fusions (12/15) exhibited an interchromosomal distribution pattern, indicating variations in the fusion formation mechanism. Importantly, our study demonstrates the substantial incremental value of RNA-NGS or other orthogonal methods in confirming the functionality of FGFR rearrangements initially identified by DNA sequencing. In our cohort, 46% (6/13) of rare FGFR1/2/3 fusions lacked detectable RNA transcripts; however, this does not definitively indicate non-functionality as factors such as low RNA quality, expression below detection limits, or nonsense-mediated decay may contribute. Therefore, RNA-based validation is critical for accurately identifying potentially targetable FGFR fusions and guiding therapy. CONCLUSION:Our findings offer critical novel insights into functional FGFR fusions and bear considerable clinical implications for identifying individuals whose tumors are most likely to respond favorably to FGFR-targeted therapies.

Therapeutic strategies for peritoneal metastasis in solid tumors are urgently needed in the clinic. Programming chimeric antigen receptor macrophages (CAR-Ms) in situ offers opportunities for an unmet demand. However, potential intracellular domains (ICDs) for CAR design and their antitumor mechanisms for macrophage empowerment remain to be explored systematically. By developing a targeted mRNA-LNP delivery system for macrophages, we have investigated 36 CAR combinations to determine the impact of CAR-Ms on immune regulation in vitro and in vivo. In two solid tumor mouse models, intraperitoneal programming of CAR-Ms was shown to elicit robust adaptive immune activation and significantly synergize with PD-1/L1 therapy. Single-cell RNA sequencing (scRNA-seq) analysis revealed that CAR-Ms could reshape the immunosuppressive tumor microenvironment (TME) and boost the TCF1+PD-1+ progenitor-exhausted CD8+ T cells (Tpex) population. Meanwhile, we found that tailored CAR-M with CD3ζ and TLR4 ICDs could favorably maintain proinflammatory phenotype and simultaneously upregulate MHC I and PD-L1 expression by perturbing NF-κB pathways. Moreover, the synergism between macrophage PD-L1 knockdown and CAR-M therapy highlights the need to block the PD-1/L1 axis in antigen cross-presentation. In short, we developed an mRNA-LNP delivery system for intraperitoneal programming of tailored CAR-Ms in vivo and broadened understanding of both regulatory and feedback mechanisms for CAR-M therapies against solid tumors. ### Competing Interest Statement The authors have declared no competing interest.

Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) provides a powerful approach to predict recurrence in colorectal cancer (CRC) and potentially improve survival outcomes for individuals diagnosed with CRC. Currently, there are two primary technical approaches for the detection of MRD using ctDNA: the tumor-informed assays and the tumor-agnostic assays. Multiple studies have demonstrated the role of MRD detection in CRC patients after radical therapy, including early relapse monitoring, molecular profiling, and treatment response prediction. Numerous interventional clinical trials based on ctDNA are underway to explore the value of MRD in optimizing adjuvant treatment decisions for patients with CRC. Once validated, ctDNA-MRD has the potential to impact current clinical treatment decisions. In this review, we summarize current techniques for detecting MRD based on ctDNA and review the data that have been collected to date on MRD detection in CRC patients who received curative-intent therapy. We also discuss prospective research of ctDNA MRD detection in this patient population and provide guidelines for the current and future use of MRD in clinical practice.

Colorectal cancer (CRC) is the most common gastrointestinal malignancy worldwide, with increasing morbidity and mortality. Heat shock transcription factor 1 (HSF1), as an important transcription factor regulating the expression of heat shock proteins, has been proven to play a crucial role in the development of various tumors. Yet the potential mechanism and clinical significance of HSF1 in CRC remain unclear and require further exploration. We used TCGA database to understand the clinical significance of HSF1 in CRC. Then, we verified the expression of HSF1 in CRC tissues by immunohistochemistry and analyzed its clinical significance. By constructing stable knockdown and overexpressed of HSF1 in cell lines to investigate the potential mechanisms of HSF1 to regulate CRC cell proliferation, migration, and invasion in vivo and in vitro. Next, differential genes expressed by HSF1 in CRC were analyzed by bioinformatics technology, and their correlation and interaction were verified by PCR, WB, and CHIP experiments. We confirmed that HSF1 is highly expressed in CRC and its upregulation is associated with poor prognosis of malignant events in CRC. Functionally, HSF1 can enhance the proliferation, invasion, and migration of CRC cell lines. In vivo experiments have shown that knockdown of HSF1 can inhibit tumor growth. In terms of molecular mechanism, we found that HSF1 can directly bind to the transcription factor binding site of CLDN3 and activate its transcription. Our research demonstrates the clinical significance and carcinogenic effect of HSF1. The functional mechanisms of HSF1 and its targets may serve as diagnostic and therapeutic targets for CRC.

BackgroundThe growing use of immune checkpoint inhibitors (ICIs) in the neoadjuvant treatment of colorectal cancer (CRC) has highlighted immune-related adverse events (irAEs) as a major concern. This study aimed to investigate the characteristics of irAEs.MethodsThis study was a retrospective, multicenter, registry-based investigation conducted in China, including 148 patients who developed irAEs after neoadjuvant immunotherapy between September 2020 and March 2024. The study analyzed the types, severity, risk factors and management strategies of irAEs. Data were collected on patient demographics, tumor assessments, neoadjuvant therapy regimens, and irAEs. Statistical analyses were conducted to identify the characteristics of irAEs and to assess their impact on surgical outcomes.ResultsAmong the 148 patients, a total of 203 irAEs were documented, primarily affecting the skin, endocrine system, and liver. Most irAEs (95.6%) were mild-to-moderate in severity and were effectively managed with symptomatic treatment. Hepatotoxicity was the most frequent irAE, notably associated with the combination of radiotherapy and the CAPOX chemotherapy regimen. The severity of irAEs did not affect surgical complexity or postoperative complications.ConclusionNeoadjuvant immunotherapy combined with chemoradiotherapy demonstrates a favorable safety profile, with most irAEs being manageable. The findings support the clinical feasibility of combined regimens in CRC treatment, emphasizing the need for individualized management and extended follow-up for late-onset or chronic irAEs.

OBJECTIVES:To investigate the role of PTEN-induced putative kinase 1 (PINK1) in regulating the viability, migration, and apoptosis of colorectal cancer (CRC) cells, and to explore its potential epigenetic mechanisms. METHODS:PINK1 was overex-pressed or knocked down in HCT116 and DLD1 CRC cell lines using lentiviral vectors, with efficiency verified by qRT-PCR and Western blotting. Cell proliferation was assessed using CCK-8 and colony formation. Cell migration was detected using wound healing and Transwell assays. Apoptosis was assessed using Hoechst 33258 staining. Protein levels of apoptosis-related and histone modification-related markers were analyzed by Western blotting. Genome-wide chromatin accessibility was profiled using assay for transposase-accessible chromatin with sequencing (ATAC-seq). RESULTS:PINK1 expression was significantly downregulated at both mRNA and protein levels in CRC tissues com-pared to normal tissues. PINK1 overexpression inhibited cell proliferation, colony formation, and migration in HCT116 and DLD1 cells (all P<0.05), whereas PINK1 knockdown promoted these malignant phenotypes (all P<0.05). PINK1 overexpression induced apoptosis, associated with decreased levels of anti-apoptotic proteins (MCL-1, BCL-2, BCL-XL) and increased pro-apoptotic BAX (all P<0.05), without altering p53 expression. Mechanistically, PINK1 overexpression reduced histone H3 lysine 9 trimethylation (H3K9me3) and histone H3 lysine 27 trimethylation (H3K27me3), and increased histone H3 lysine 9 acetylation (H3K9ac) and histone H3 lysine 27 acetylation (H3K27ac). It also downregulated key histone-modifying enzymes, including enhancer of Zeste homolog (EZH)2, EZH1, SUZ12, and histone deacetylase 3 (HDAC3) (all P<0.01). ATAC-seq revealed that PINK1 overexpression increased chromatin accessibility, particularly around transcription start sites. CONCLUSIONS:PINK1 acts as a tumor suppressor in colorectal cancer by inhibiting proliferation and migration, promoting apoptosis, and remodeling the epigenetic landscape through altering histone modifications and enhancing chromatin accessibility.

To assess the effect of computed tomography angiography (CTA) and three-dimensional (3D) reconstruction on laparoscopic colectomy in patients with colon cancer. Patients with colon cancer who were treated at Zhejiang Cancer Hospital between August 2020 and December 2022 were included in this pilot, randomized controlled trial. The participants were randomly assigned to either the CTA group, in which patients underwent preoperative CTA and 3D reconstruction, or the control group, in which patients underwent preoperative enhanced abdominal and pelvic CT examinations. The primary outcome was the duration of the operation. The secondary outcomes included intraoperative blood loss, length of hospital stay, number of lymph node dissections, fasting duration, duration of tube drainage, overall survival (OS), and progression-free survival (PFS). To minimize statistical bias, patients were stratified into subgroups on the basis of tumor location (left colon or right colon). Additionally, variations in the middle colonic artery (MCA), inferior mesenteric artery (IMA), and colonic branches of superior mesenteric artery (cbSMA) classifications were documented. A total of 82 patients (41 in each group) were included in the analysis. The CTA group had significantly shorter operation durations (123.68 ± 26.09 vs. 154.12 ± 33.15 min, P < 0.001) and fasting durations (median 4.00 vs. 5.00 days, P < 0.001) as well as reduced intraoperative blood loss (median 50.00 vs. 100.00 mL, P = 0.001) compared to the control group; these differences were observed in the overall colon cancer cohort and in the left and right colon subgroups. However, no significant differences were observed between the two groups in terms of lymph node dissection, tube drainage duration, hospitalization duration, OS or PFS. In the CTA group, the proportions of patients with different IMA types were as follows: Type A (60.97

This study investigated the role of C-X-C motif chemokine receptor 6 (CXCR6) in colorectal cancer (CRC). It was found that lower CXCR6 expression is correlates with poorer prognostic outcomes, suggesting that CXCR6 may inhibit tumor progression and thus improve patient outcomes. Silencing CXCR6 in CRC cell lines SW620 and CT-26 resulted in significantly enhanced migration and invasion, as demonstrated by wound healing and transwell assays. Further analysis revealed that CXCR6 activity is associated with activation of the VEGFA/PI3K/AKT/mTOR signaling pathway. Inhibition of this pathway through VEGFA siRNA and pathway-specific inhibitors reversed the effects of CXCR6 silencing on cell migration and invasion. Moreover, xenograft experiments showed that silencing CXCR6 led to increased tumor growth and upregulated proteins associated with the extracellular matrix and epithelial-mesenchymal transition. These findings were validated through immunohistochemical, immunofluorescence, and Western blot analyses. This study highlights CXCR6's critical role in CRC and its potential as a therapeutic target to manage cancer progression.