Therapeutic resistance represents a formidable bottleneck in colorectal cancer (CRC) management, severely limiting the clinical efficacy of both conventional regimens and novel immunotherapies. Emerging evidence underscores tertiary lymphoid structure (TLS) - ectopic lymphoid aggregates newly sculpted within the tumor microenvironment (TME) - as pivotal orchestrators of localized antitumor immunity and prime therapeutic targets to circumvent resistance. Distinct from secondary lymphoid organs, TLS facilitate in situ immune cell priming, clonal expansion, and functional differentiation, thereby sustaining a robust adaptive immune response. This review systematically dissects the cellular architecture, maturation dynamics, and spatial heterogeneity of TLS in primary and metastatic CRC, clarifying how these attributes dictate clinical outcomes and treatment responsiveness. Mechanistically, we delineate the molecular networks driving TLS neogenesis, encompassing chemokine cascades, tumor necrosis factor (TNF) superfamily signaling, and interactive crosstalk with the gut microbiota. Furthermore, we summarize cutting-edge preclinical strategies - including stimulator of interferon genes agonists, bio-nanovaccines, and hypofractionated radiotherapy combinations - engineered to trigger TLS neogenesis, promote germinal center (GC) maturation, and enrich stem-like effector tumor-infiltrating lymphocytes (TILs) to convert immunologically “cold” tumors into “hot” niches. By integrating mechanistic paradigms with clinical applications, this review provides a definitive framework for leveraging TLS targeting as a transformative modality to modulate drug resistance and optimize therapeutic trajectories in CRC; the graphical abstract is shown below.

Colorectal cancer (CRC) exhibits pronounced biological diversity, a feature increasingly attributed to alterations in cellular metabolic reprograms. Serine metabolism supports nucleotide synthesis, redox balance, and epigenetic regulation via one-carbon metabolism, yet its role in shaping the tumor cellular interactions and immune landscape at single-cell level remains unclear. Single-cell transcriptomic profiles (GSE284449) were jointly analyzed with bulk expression datasets (GSE271719), together with Mendelian randomization (MR)-based inference, to dissect serine metabolism in CRC. High-serine-metabolism (HSM) cell populations were identified using scMetabolism, and robust marker genes were selected through Lasso, random forest, XGBoost, and SVM-RFE machine learning approaches. MR was applied to evaluate causal associations with CRC risk. Functional validation included IHC, qRT-PCR, western blot, and LC–MS metabolomics, while CellChat analysis characterized HSM cell interactions with immune and stromal cells. ZBTB21 and TRPM2 were identified as core regulators of HSM cells, with ZBTB21 predominantly expressed in monocytes and pro-B cells. MR analysis suggested a potential inverse association between genetically predicted ZBTB21 expression and CRC risk, indicating that ZBTB21 may exert context-dependent effects at the population level. Cell–cell communication analysis suggested that HSM monocytes may interact with fibroblasts through signaling pathways including the MIF–SPP1 axis; however, these interactions are computationally inferred and require further experimental validation. Functional assays showed that ZBTB21 overexpression upregulated PHGDH and SHMT1, increased intracellular NADPH/NADP⁺ ratios, and influenced monocyte-related phenotypes. ZBTB21 levels were markedly increased in CRC samples relative to matched non-tumorous mucosal tissues. At single-cell resolution, ZBTB21 emerges as a metabolic regulator that strengthens serine biosynthesis and redox homeostasis. While integrative analyses suggest a potential link between ZBTB21-associated metabolic states and immune interactions, further experimental validation is required to establish causal relationships. This integrative framework connects genetic causality, metabolism, and immune interactions, providing mechanistic insights and potential strategies for metabolic-targeted therapies in CRC. Trial registration: Not applicable.

LBA3563 Background: The optimal second-line treatment for metastatic colorectal cancer (mCRC) after failure of oxaliplatin-based chemotherapy therapy remains an area of active research, while bevacizumab combined with chemotherapy is a standard option. Fruquintinib (Fru) is a highly selective and potent oral tyrosine kinase inhibitor of VEGFR 1, 2, and 3. This study aimed to compare the efficacy and safety of fruquintinib combined with chemotherapy versus bevacizumab combined with chemotherapy as second-line treatment for mCRC. Methods: This was a non-inferiority trial conducted across 12 hospitals and cancer centers in China. Patients with mCRC who had progressed on fluoropyrimidine and oxaliplatin-based first-line chemotherapy therapy were randomly assigned (1:1) to receive either Fru (4 mg orally, once daily for 3 weeks on/1 week off) plus FOLFIRI, or bevacizumab (Bev) (5 mg/kg intravenous, every 2 weeks) plus FOLFIRI. Randomization was stratified by primary tumor location and RAS/BRAF status. During combination therapy, pts who achieve disease control after 4-6 months of treatment proceeded to maintenance therapy, receiving either fruquintinib combined with capecitabine or bevacizumab combined with capecitabine. The primary endpoint was progression-free survival (PFS). Final analysis occurred after either 97 PFS events or after the last patient had completed 12 months of follow-up, whichever occurred first. The non-inferiority upper margin of HR was 1.33. Results: Between Jul 13, 2023, and Mar 4, 2025, 122 pts were enrolled and randomly assigned to the Fru group (n=60) or the Bev group (n=62). The median age was 59.0 (IQR 54-69) and 60.0 (IQR 51-70) years, 45 (75%) and 48 (77%) had left-sided tumors, 36 (60%) and 36 (58%) were RAS/BRAF mutant, respectively. At data cut-off (Feb 28, 2026), the median PFS of the Fru group was non-inferior to the Bev group, whether in the Intention to Treat Population (ITT) (9.40 vs 7.39 months, hazard ratio [HR]=0.806 [95% CI 0.522–1.244, 80% CI 0.607-1.07]; p=0.33) or the per-protocol set (PPS) (9.49 vs 7.85 months, HR=0.848 [95% CI 0.542–1.326, 80% CI 0.633-1.136]; p=0.469). In the subgroup analysis , the Fru group showed longer PFS in prior never used VEGF inhibitor pts (10.6 vs 8.5 months, HR=0.94, 95% CI 0.54-1.62), and pts without liver metastasis (14.5 vs 9.9 months, HR=0.97, 95% CI 0.43-2.22) compared to the Bev group. The objective response rate was 35.0% with Fru vs 22.6% with Bev group. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100.0% (Grade ≥3, 28.1%) of the Fru group and 93.2% (Grade ≥3, 28.8%) of the Bev group. Conclusions: Fruquintinib combined with FOLFIRI demonstrated non-inferiority in PFS compared with bevacizumab combined with FOLFIRI as a second-line treatment for mCRC, with a manageable safety profile. Clinical trial information: NCT05555901 .

BACKGROUND:The efficacy of single-incision laparoscopic surgery (SILS) for colorectal cancer remains controversial due to uncertainties regarding long-term outcomes. This study aimed to compare the 5-year outcomes of SILS and conventional laparoscopic surgery (CLS) for colorectal cancer in a randomized clinical trial. METHODS:This trial was a single-center, open-label, non-inferiority, randomized clinical trial conducted at our hospital. Patients aged 18-85 years who were diagnosed with or suspected of having colorectal cancer (staged cT1-4aN0-2M0) were enrolled. Neither the patients nor investigators were blinded to treatment allocation. The final follow-up date was on August 1, 2024. Participants were randomly assigned to either the SILS or CLS group in a 1:1 ratio using the random number table method. Both groups underwent surgery following the same oncological principles, including complete mesocolic excision for colon cancer and total mesorectal excision for rectal cancer with D3 lymph node dissection. The primary outcome was the early morbidity rate, which was reported previously. Here, we primarily report the long-term outcomes analyzed in the modified intention-to-treat (mITT) population, including 5-year disease-free survival (DFS), overall survival (OS), incisional hernia incidence, and recurrence patterns. RESULTS:A total of 200 patients were enrolled between June 28, 2017 and June 29, 2019. Of these, 193 (110 men [57.0%]; median (interquartile range [IQR]) age, 64 [15] years) were included in the mITT analysis. No patients were lost to follow-up within 5 years postoperatively. The median follow-up was 71.3 months (IQR 64.2-76.8). The 5-year DFS was 86.6% in the SILS group and 86.5% in the CLS group (hazard ratio, 1.03 [95% CI 0.47-2.21], P = 0.95). The 5-year OS rates were 88.7% and 90.6% in the SILS and CLS groups, respectively (hazard ratio, 1.26 [95% CI 0.52-3.02], P = 0.61). No statistically significant differences were observed between the two groups in terms of recurrence patterns, incisional hernia incidence, or recurrence and survival rates stratified by tumor stage. CONCLUSIONS:SILS, when performed by experienced surgeons, can be considered a promising alternative for selected colorectal cancer patients. This potentially expands the range of surgical treatment options available to both patients with colorectal cancer and surgeons.

Ubiquitin conjugating enzyme UBE2S is an important enzyme in ubiquitin mediated proteolysis. The mechanisms of UBE2S in the colorectal cancer (CRC) proliferation need further exploration for new ubiquitination-related drugs exploitation. Firstly, we performed immunohistochemistry of UBE2S protein on CRC and adjacent tissues and found that UBE2S protein expressed higher in adjacent tissues than in tumor. TCGA and GTEx databases revealed a positive correlation between UBE2S expression and overall survival rate in CRC (P < 0.05). Cell proliferation experiments on HCT116 and RKO cell lines invalidated that UBE2S overexpression inhibited CRC cell proliferation and progression from G0/1 phase to G2 phase while knocking down UBE2S enhanced it. Mechanistically, combined with enrichment analysis based on RNA sequencing, it was identified molecularly that UBE2S simultaneously inhibited the activation of MAPK/ERK and PI3K/AKT pathways through promoting the ubiquitin-mediated degradation of TRAF6 protein, an upstream molecule to activate the both pathways, which can be blocked by inhibitor MG132. Animal experiments demonstrated that knocking down UBE2S resulted in larger transplanted tumor volumes than the control group, while overexpressing UBE2S resulted in the smaller ones in vivo. Summarily, we firstly identified that the UBE2S inhibited CRC proliferation by negatively regulating MAPK/ERK and PI3K/AKT/mTOR pathways through ubiquitinating TRAF6 protein.

3589 Background: Single-incision laparoscopic surgery (SILS) is increasingly being embraced in the medical community due to its potential to offer less-invasiveness and quick recovery. This multi-center randomized controlled trial compared the short-term and long-term outcomes of single-incision laparoscopic surgery (SILS) with conventional laparoscopic surgery (CLS) for colorectal cancer, which might be the first of its kind that involved both colon and rectal cancer. Study recruitment has completed, and the follow-up is ongoing. Here we report the short-term outcomes of this trial. Methods: The trial was conducted across 11 hospitals in 6 provinces of China. Participants included patients with histologically confirmed colorectal carcinoma that situated above the peritoneal reflection, clinically staged as I-III. Patients were randomly assigned in a 1:1 ratio to SILS or CLS group. Comprehensive perioperative data were meticulously gathered, and follow-up assessments were scheduled postoperatively. The primary endpoint was 3-year disease-free survival (DFS), secondary endpoints included overall survival (OS), oncological efficacy, and postoperative outcomes. Results: Between May 2021 and April 2023, a total of 712 patients were randomly assigned to either the Single-incision Laparoscopic Surgery (SILS) group (n = 354) or the Conventional Laparoscopic Surgery (CLS) group (n = 358). The distribution of surgical procedures included 162 (22.8%) right hemicolectomies, 326 (45.8%) left hemicolectomies, and 224 (31.4%) proctectomies. The pathological TNM stages I, II, and III of the mITT population were 10.7%, 36.9%, and 52.4%, respectively. In the SILS group, 92.9% (n = 329) of the cases were completed entirely with a single incision. An additional trocar was used to assist the surgical procedure in 5.6% (n = 20) of the cases, and 0.8% (n = 3) were converted to conventional laparoscopic surgery. Two patients in the SILS group required conversion to open surgery, compared to 10 patients in the CLS group. The incidence of postoperative complications and oncological efficacy were statistically equivalent between the two groups. Moreover, patients in the SILS group reported significantly less postoperative pain (p = 0.02). There were no significant differences in short-term overall survival (OS) and disease-free survival (DFS) between the two arms. Conclusions: Single-incision laparoscopic surgery (SILS) for colorectal cancer has demonstrated with feasibility, safety, and efficacy. The less painful postoperative experience was aligned with the principles of Enhanced Recovery After Surgery (ERAS). This surgical approach extended the concept of minimally invasiveness and represents a logical progression towards Natural Orifice Transluminal Endoscopic Surgery (NOTES) or single-incision robotic surgery. Clinical trial information: NCT04527861 .

Robotic surgery for rectal cancer is widely used, but data on long-term oncological outcomes are still lacking. To compare the 3-year locoregional recurrence rates of middle and low rectal cancer in patients who underwent robotic surgery vs conventional laparoscopic surgery. In this multicenter, superiority, randomized clinical trial, patients with middle or low rectal adenocarcinoma (cT1-T3, N0-N1, or ycT1-T3 Nx) and no distant metastasis were enrolled at 11 centers across 8 provinces in China from July 2016 to December 2020. Among the 1742 consecutive patients assessed for eligibility, 1240 were eligible and randomized. Follow-up continued until December 31, 2023. Patients were randomized 1:1 to undergo robotic or conventional laparoscopic rectal cancer resection. The primary outcome was the 3-year locoregional recurrence rate. The primary analysis was performed as randomized, but excluded patients deemed ineligible after randomization. The secondary outcomes included disease-free survival; overall survival; and urinary, sexual, and defecation function. Of the 1240 patients enrolled, 1171 were included in the primary analysis (586 in the robotic surgery group; mean age, 59.1 [SD, 11.0] years; and 356 were men [60.8%] vs 585 in the laparoscopic surgery group; mean age, 60.7 [SD, 9.8] years; and 354 were men [60.5%]). The median follow-up time was 43.0 months (IQR, 36.7-60.0 months). The 3-year locoregional recurrence rate was 1.6% (95% CI, 0.6%-2.6%) in the robotic group vs 4.0% (95% CI, 2.4%-5.6%) in the laparoscopic group (hazard ratio [HR], 0.45 [95% CI, 0.22-0.92], log-rank P = .03; adjusted HR, 0.39 [95% CI, 0.19-0.80]). The 3-year disease-free survival rate was higher in the robotic group (87.2%) vs the laparoscopic group (83.4%) (HR, 0.74 [95% CI, 0.56-0.98], log-rank P = .04; adjusted HR, 0.67 [95% CI, 0.50-0.89]). No significant between-group difference was observed in 3-year overall survival (94.7% in the robotic group vs 93.0% in the laparoscopic group). Patients in the robotic group also had better urinary function, male and female sexual function, and defecation function at 3 and 6 months after surgery and better urinary function and male sexual function at 12 months after surgery. Compared with conventional laparoscopic surgery, robotic surgery significantly improved long-term oncological outcomes in patients with middle or low rectal cancer. With additional real-world clinical data and modern, improved training programs for surgeons, robotic surgery could be the preferred choice for patients with middle or low rectal cancer. ClinicalTrials.gov Identifier: NCT02817126.

Importance Robotic surgery for rectal cancer is widely used, but data on long-term oncological outcomes are still lacking. Objective To compare the 3-year locoregional recurrence rates of middle and low rectal cancer in patients who underwent robotic surgery vs conventional laparoscopic surgery. Design, Setting, and Participants In this multicenter, superiority, randomized clinical trial, patients with middle or low rectal adenocarcinoma (cT1-T3, N0-N1, or ycT1-T3 Nx) and no distant metastasis were enrolled at 11 centers across 8 provinces in China from July 2016 to December 2020. Among the 1742 consecutive patients assessed for eligibility, 1240 were eligible and randomized. Follow-up continued until December 31, 2023. Interventions Patients were randomized 1:1 to undergo robotic or conventional laparoscopic rectal cancer resection. Main Outcomes and Measures The primary outcome was the 3-year locoregional recurrence rate. The primary analysis was performed as randomized, but excluded patients deemed ineligible after randomization. The secondary outcomes included disease-free survival; overall survival; and urinary, sexual, and defecation function. ResultsOf the 1240 patients enrolled, 1171 were included in the primary analysis (586 in the robotic surgery group; mean age, 59.1 [SD, 11.0] years; and 356 were men [60.8%] vs 585 in the laparoscopic surgery group; mean age, 60.7 [SD, 9.8] years; and 354 were men [60.5%]). The median follow-up time was 43.0 months (IQR, 36.7-60.0 months). The 3-year locoregional recurrence rate was 1.6% (95% CI, 0.6%-2.6%) in the robotic group vs 4.0% (95% CI, 2.4%-5.6%) in the laparoscopic group (hazard ratio [HR], 0.45 [95% CI, 0.22-0.92], log-rank P = .03; adjusted HR, 0.39 [95% CI, 0.19-0.80]). The 3-year disease-free survival rate was higher in the robotic group (87.2%) vs the laparoscopic group (83.4%) (HR, 0.74 [95% CI, 0.56-0.98], log-rank P = .04; adjusted HR, 0.67 [95% CI, 0.50-0.89]). No significant between-group difference was observed in 3-year overall survival (94.7% in the robotic group vs 93.0% in the laparoscopic group). Patients in the robotic group also had better urinary function, male and female sexual function, and defecation function at 3 and 6 months after surgery and better urinary function and male sexual function at 12 months after surgery. Conclusions and Relevance Compared with conventional laparoscopic surgery, robotic surgery significantly improved long-term oncological outcomes in patients with middle or low rectal cancer. With additional real-world clinical data and modern, improved training programs for surgeons, robotic surgery could be the preferred choice for patients with middle or low rectal cancer.

Data scarcity remains a fundamental barrier to achieving fully autonomous surgical robots. While large scale vision language action (VLA) models have shown impressive generalization in household and industrial manipulation by leveraging paired video action data from diverse domains, surgical robotics suffers from the paucity of datasets that include both visual observations and accurate robot kinematics. In contrast, vast corpora of surgical videos exist, but they lack corresponding action labels, preventing direct application of imitation learning or VLA training. In this work, we aim to alleviate this problem by learning policy models from Cosmos-H-Surgical, a world model designed for surgical physical AI. We curated the Surgical Action Text Alignment (SATA) dataset with detailed action description specifically for surgical robots. Then we built Cosmos-H-Surgical based on the most advanced physical AI world model and SATA. It's able to generate diverse, generalizable and realistic surgery videos. We are also the first to use an inverse dynamics model to infer pseudokinematics from synthetic surgical videos, producing synthetic paired video action data. We demonstrate that a surgical VLA policy trained with these augmented data significantly outperforms models trained only on real demonstrations on a real surgical robot platform. Our approach offers a scalable path toward autonomous surgical skill acquisition by leveraging the abundance of unlabeled surgical video and generative world modeling, thus opening the door to generalizable and data efficient surgical robot policies.

BACKGROUND:Tertiary lymphoid structures (TLS) are emerging biomarkers for enhanced anti-tumoral immunity and treatment efficacy in colorectal cancer (CRC). This study aimed to develop a CRC-specific TLS signature and evaluate its predictive roles in survival prognosis and therapeutic responses to chemotherapy, and PD-1 blockade. MATERIALS AND METHODS:Transcriptomic data from TCGA database were analyzed to establish a TLS signature. Survival and treatment responses were validated in multiple cohorts, including TCGA cohort, RJ cohort (neoadjuvant FOLFOX, n = 16), CHcohort (neoadjuvant sintilimab, n = 17), and several GEO datasets. Genetic mutations, tumor microenvironment (TME) features, and its spatial interactions were assessed via maftools, Bayesprism, CIBERSORT, IBOR, TIMER 2.0, NicheNet analysis and multiplex immunofluorescence. Tumor-immune cells co-cultured miniPDX/PDO models were used to validate PD-1 blockade in MSS CRC. RESULTS:In TCGA cohort, patients in TLS_high group exhibited significantly longer overall survival ( P = 0.008) and demonstrated a higher proportion of complete response/partial response (CR/PR) ( P = 0.017). Further analyses on TME revealed that tumor mutation burden was positively correlated with TLS signature scores ( R = 0.31, P < 0.001). High TLS scores depicted a higher proportion of CD8 + T cells, B cells, and dendritic cells, increased activation of anti-tumoral signaling pathways, enhanced cytokines secretion, and higher immune checkpoints expression, including CTLA4, LAG3, and TIM3. Sensitive group in RJ cohort and clinical CR group in CH cohort scored higher of TLS signature ( P < 0.05), and depicted activation of signaling pathways related to TLS formation. Mature TLS and enhanced intercellular receptor-ligand interactions were identified. miniPDX/PDO models confirmed TLS-driven PD-1 blockade sensitivity in MSS CRC. CONCLUSIONS:The CRC-specific TLS signature identifies patients with favorable prognosis and enhanced responses to chemotherapy and PD-1 blockade, including MSS CRC resistant to immune checkpoint blockade. TLS abundance reflects an immunogenic TME, offering a biomarker for personalized treatment strategies.

BACKGROUND:Minimally invasive surgery, particularly robotic-assisted platforms like the da Vinci systems, has revolutionized colorectal surgery by improving precision and recovery. The novel da Vinci Single-Port (SP) system enables procedures through a single incision, offering potential advantages over multiport systems. Following its 2023 clinical authorization in China via Hainan's special policy, this study evaluates the application of SP system in colorectal surgery within the Chinese population. OBJECTIVE:To assess the perioperative safety, feasibility, and short-term oncological outcomes of the da Vinci SP system for diverse colorectal procedures. METHODS:A preliminary non-comparative exploratory study (NCT06141421) enrolled 15 patients who received SP colorectal surgery from October 2023 to July 2024. Procedures included transanal endoscopic microsurgery (TEM), proctectomy, hemicolectomy, sigmoidectomy, and total colectomy. Primary endpoint: intraoperative conversion rate. Secondary endpoints: Clavien-Dindo ≥III complications within 30 days. Data collected: operative time (OT), blood loss (EBL), length of stay (LOS), pain scores (VAS), complications, resection margins, lymph node yield, and 12-month recurrence/mortality. RESULTS:All 15 procedures (53.3% male; 46.7% prior abdominal surgery) were completed without conversion. Median OT: 119 min (transabdominal: 129 min; TEM: 89 min). Median EBL: 10 mL (transabdominal: 20 mL; TEM: 3 mL). Median LOS: 12 days (transabdominal: 14 days; TEM: 4 days). VAS pain scores were low (Day 1: 3; Day 3: 2). Three Clavien-Dindo II complications occurred (2 anastomotic leaks, 1 infection; no ≥III events). All 12 malignancies achieved R0 resection; median lymph nodes harvested: 13.5. No recurrence, metastasis, or mortality at 12-month follow-up. CONCLUSIONS:The da Vinci SP system is feasible and safe for diverse colorectal procedures, demonstrating zero conversions, minimal blood loss, acceptable operative times, and favorable short-term oncological outcomes. Limitations include small sample size and prolonged LOS (attributed to logistical factors). Larger multicenter studies are needed to validate long-term efficacy and cost-effectiveness.

T cell dysfunction with age underlies an increased incidence of cancer in elderly individuals; however, how T cell aging is triggered in the tumor microenvironment is unclear. Here, we show that an age-associated reduction in adipocyte-derived leptin contributes to the accumulation of tumor-infiltrating senescent CD8+ T cells. Single-cell profiling of human and mouse cancer tissues reveals that the frequency of intratumoral senescent CD8+ T cells increases with age, leading to a weak antitumor effect. Moreover, decreased levels of adipocyte-derived leptin are an indispensable factor for CD8+ T cell aging. Leptin signaling prevents p38-dependent CD8+ T cell senescence. Furthermore, plasma leptin levels are negatively related to intratumoral CD8+ T cell senescence in cancer patients. Our findings identify an unappreciated interplay between metabolic perturbation and T cell aging and suggest that modulating adipocyte-derived leptin levels may be a promising therapeutic strategy for older cancer patients.

Objective This study analysed the causal relationships between free cholesterol-to-total lipid ratios in different very low-density lipoprotein (VLDL) subfractions and the risk of colorectal cancer (CRC) via a two-sample Mendelian randomization (MR) approach. Methods Genetic variants associated with free cholesterol-to-total lipid ratios in chylomicrons, as well as extremely large, very large, large, medium, small, and very small VLDL subfractions, were identified from genome-wide association studies and selected as instrumental variables. Five analytical methods, including inverse variance weighted (IVW), MR‒Egger, weighted median, weighted mode, and simple mode, were implemented for MR analysis. Results Elevated free cholesterol-to-total lipid ratios in very large VLDL (odds ratio (OR) ​= ​1.25; 95%CI: 1.06–1.49; P ​= 0.01), medium VLDL (OR ​= ​1.20; 95%CI: 1.04–1.40; P ​= 0.015), small VLDL (OR=1.17; 95%CI: 1.01–1.35; P ​= 0.038), and very small VLDL (OR ​= ​1.29; 95%CI: 1.08–1.54; P ​= 0.005) subfractions were found to be associated with an increased risk of CRC. No significant associations were detected between the risk of CRC and the free cholesterol-to-total lipid ratios in chylomicrons or the extremely large VLDL subfraction. Conclusions MR analysis provided evidence for a causal association between elevated free cholesterol-to-total lipid ratios in very large, medium, small, and very small VLDL subfractions and an increased risk of CRC. These findings suggest the potential mechanistic role of altered VLDL metabolism in colorectal carcinogenesis and may inform novel therapeutic and preventive strategies.

The National Health Commission of the People's Republic of China Guidelines for Diagnosis and Treatment of Colorectal Cancer (2025 edition), based on evidence-based medicine, integrates cutting-edge international advances with Chinese clinical practice, and supplements and completes the previous versions. This version of the guidelines, retains the core diagnostic and treatment framework, highlights new contents such as "Surgical treatment of anal canal cancer" and "New technologies and advances in diagnosis and treatment", and systematically summarizes the core points in the surgical treatment, medical oncology treatment, radiation oncology treatment, imaging, and pathology treatment. It is designed to help clinicians quickly grasp the key points of the guidelines and promote the standardization, precision, and consistence of colorectal cancer diagnosis and treatment.

e15617 Background: The abdominal incisions after laparoscopic colorectal cancer surgery remain to bother surgeons and patients due to cosmetic concerns, potential scarring and related complications. Total transvaginal natural orifice endoscopic surgery (total v-NOTES) has emerged as a totally scarless and promising alternative. This cohort pilot study endeavors to evaluate the safety, feasibility, and long-term survival outcomes of employing total v-NOTES in the management of colon cancer for female patients. Methods: This non-randomized prospective cohort pilot study involved seven female patients who underwent total v-NOTES from September 2020 to January 2021 for Stage II or III colon cancer in our hospital. Demographic information, perioperative outcomes and oncological outcomes were recorded. Subsequently, overall survival (OS) was defined as the time period from surgery until death or loss of follow-up, and disease-free survival (DFS) was defined as the period from surgery until signs or symptoms of cancer, or loss of follow-up. 3-year OS and DFS were obtained from all patients. Results: For perioperative outcomes, the surgeries were successfully executed for all 7 patients via the transvaginal route, with no conversions to regular laparoscopic surgery. The median operative time was 275 minutes and the median estimated blood loss was 100 ml. No grade III or above postoperative complications by Clavien-Dindo grading were reported, and there were no readmissions within the 30-day postoperative period. For oncological outcomes, all patients achieved R0 resections, with no positive distal margin or circumferential margin. At least 12 lymph nodes were retrieved from all cases with a median of 14 harvested lymph nodes. At the 3-year follow-up, survival was maintained in all patients, with no instance of recurrence or metastasis. Conclusions: Total v-NOTES is a feasible and safe approach for selected patients with colon cancer, offering satisfactory perioperative and long-term outcomes. While these results are encouraging, further large-scale studies are essential to confirm its potential as a viable alternative to traditional laparoscopic surgery. Clinical trial information: NCT04527861 .

Colorectal cancer (CRC) is one of the deadliest malignancies worldwide characterized by rapid progression, high metastasis propensity. Our study aimed to identify the driving biological factors of metastatic CRC. We obtained frozen tumor tissues of 8 metastatic CRC (mCRC) patients and 10 non-metastatic CRC (nmCRC) patients from Ruijin Hospital for proteome analysis. FFPE tumor and adjacent normal tissues of another 8 metastatic CRC patients and 8 non-metastatic CRC patients were collected for transcriptome and whole exome sequencing. Mutational burden and signatures were revealed and differentially expressed genes and proteins were analyzed. Molecular Complex Detection was used to build the core network. KEGG and GO pathway enrichment analysis were performed. IHC staining against p-RPS6 and subsequent quantification were performed on human samples. We identified 53,917 SNPs by WES with a median of 1154 variants per sample and 23.08 mutations per megabase (Mb). We observed the mutation burdens were similar between mCRC tumor and nmCRC tumor tissues (p = 0.57), as well as the mutation frequencies of HRR and MMR related genes. All mCRC samples were affected by RTK-RAS, NOTCH and WNT pathway mutations. We constructed a 16-hub-gene network in mCRC which was characterized by dis-modulation of cell adhesion (SELE, SELL and SELP) and immune exhaustion (CXCR2, CCR7, CXCR1, CXCL13, CCL7, CCL19, CXCL11 and CD19) in mCRC tumor microenvironment. We detected 22 differentially expressed proteins, 54 phosphorylated proteins and 6 tyrosine-phosphorylated proteins between mCRC and nmCRC tumors. Phosphorylated RPS6 (p-RPS6) was the most differentially expressed protein between mCRC and nmCRC tumor tissues, which was found to be positively correlated with EMT proteins and poor prognosis in CRC. The IHC staining against p-RPS6 on human samples supported the strong expression in mCRC tumor samples. We identified the key transcriptome network in mCRC and confirmed the important role for RPS6 phosphorylation in mCRC. Our study suggested that the features of mCRC tumors were not driven by gene mutations. We revealed the EMT feature and immune exhaustion of the mCRC tumor microenvironment.

Dietary nutrients are inextricably linked to antitumour immune responses. However, the effect of diet-derived galactose on antitumour immunity remains unclear. Here we show that dietary galactose augments CD8+ T cell immunity to suppress tumour progression. High-galactose feeding drives hepatocyte-derived insulin-like growth factor binding protein 1 (IGFBP-1) production, thus restraining IGF-1 signalling-dependent T cell exhaustion. IGF-1 receptor (IGF-1R) deficiency in T cells potentiates antitumour CD8+ T cell responses and phenocopies high-galactose feeding by preventing T cell exhaustion. Circulating galactose reprograms hepatocyte metabolism to inactivate mTORC1, thereby inducing the production of IGFBP-1 to boost CD8+ T cell function. Furthermore, patients with cancer who have high plasma IGFBP-1 levels exhibit blocked T cell exhaustion and enhanced T cell responses in tumour tissues. These findings reveal that dietary galactose specifically elicits potent antitumour CD8+ T cell responses by facilitating hepatocyte-derived IGFBP-1 production, providing insights into the development of more effective immunotherapies against cancers.

Background:Surgical start time is considered to influence the quality of surgery due to surgeon fatigue. High-quality studies on middle and low rectal cancer are lacking. The analysis aims to find out the influence of surgical start time on the quality of surgery for middle and low rectal cancer, and whether robotic surgery could avoid the influence.Materials and methods:This study was a post hoc analysis of the REAL (robotic vs. laparoscopic surgery for middle and low rectal cancer) study, a multicenter, randomized, controlled, unblinded, parallel group, superiority trial. This analysis included the modified intention-to-treat population of the REAL study, who were divided into Group I (the surgeon's first surgery of the day), Group II (the surgeon's second surgery of the day), and Group III (the surgeon's third and subsequent surgeries of the day) based on surgical information registered in the REAL study. The primary outcome was the percentage of patients with a positive circumferential resection margin. The second outcomes were the macroscopic completeness of resection the incidence of intraoperative complications and 30-day postoperative complications.Results:A total of 1171 patients from the REAL study were included and divided into three groups: 547 (46.7%) in Group I (the surgeon's first surgery), 420 (35.9%) in Group II (the surgeon's second surgery), and 204 (17.4%) in Group III (the surgeon's third and subsequent surgeries). There was a lower percentage of circumferential resection margin (CRM)-positive patients in Group I (3.9%) than in Group II (6.6%, unadjusted P = 0.069) and Group III (8.1%, unadjusted P = 0.027, adjusted P = 0.081). Group I also had fewer intraoperative complications (5.3%) than Group II (8.3%, unadjusted P = 0.060) and Group III (9.3%, unadjusted P = 0.046, adjusted P = 0.138). Macroscopic completeness of resection was not significantly different among the three groups (complete rate: Group I vs. Group II, 94.9% vs. 92.4%, unadjusted P = 0.254; Group I vs. Group III, 94.9% vs. 92.6%, unadjusted P = 0.334; Group II vs. Group III, 92.4% vs. 92.6%, unadjusted P = 0.488). The incidence of 30-day postoperative complications showed no significant difference among the three groups (Group I vs. Group II, 18.5% vs. 20.0%, unadjusted P = 0.547; Group I vs. Group III, 18.5% vs. 22.1%, unadjusted P = 0.268; Group II vs. Group III, 20.0% vs. 22.1%, unadjusted P = 0.551). The quality of robotic surgery was not significantly influenced by surgical start time. For laparoscopic surgery, Group I had a lower CRM positivity rate (4.3%) than Group II (9.4%, unadjusted P = 0.029, adjusted P = 0.087) and Group III (10.4%, unadjusted P = 0.031, adjusted P = 0.047).Conclusion:According to this post hoc analysis of the REAL study, for middle and low rectal cancer surgery, surgical start time could influence surgical quality by affecting surgeon fatigue. Surgeries start later in a day bring worse quality compared to those early in a day. Robotic surgery could reduce this influence to some extent, while laparoscopic surgery is more susceptible.