Cancer immunotherapies have revolutionized cancer treatment, yet many patients fail to respond. Activating innate immunity offers a promising approach to enhance therapeutic efficacy, but the signaling kinases directly regulating this process to boost antitumor responses remain elusive. Here we conduct an in vivo kinome CRISPR screen and identify CDK10 as a key suppressor of tumor immune surveillance. Mechanistically, CDK10 phosphorylates DNMT1 and RAP80 to reduce the accumulation of double-stranded RNA and R-loops, which alleviates the activation of innate immune pathways mediated by MDA5 and cGAS. Kinase inhibitor screens identify NVP-AST487 and ponatinib as selective CDK10 inhibitors. Both genetic and pharmacological inhibition of CDK10 activates MDA5 and cGAS pathways, fostering an immunoactive tumor microenvironment that enhances cancer immunotherapy in multiple mouse tumor models. Clinically, low CDK10 expression in tumors correlates with better immunotherapy responses. These findings establish CDK10 as a pivotal modulator of tumor immunity and a potential therapeutic target. Xu et al. report that CDK10 drives immune evasion by reducing nucleic acid sensors-mediated innate immune response in tumor cells and that its inhibition improves response to immune-checkpoint blockade in preclinical cancer models.

Background: Although cancer immunotherapies have revolutionized cancer treatment, a substantial proportion of patients remain unresponsive. Elucidating the molecular mechanisms underlying tumor immune evasion and identifying key regulators are essential for improving immunotherapy efficacy. NOP2/Sun RNA methyltransferase 2 (NSUN2) exhibits widespread mutations across pan-cancer cohorts. This study aimed to delineate the noncanonical functions of NSUN2 in cancer immune modulation and explore its potential as a therapeutic target for cancer immunotherapy. Methods: Multiple cancer cells expressing catalytically inactive NSUN2 mutants were generated and subjected to in vitro functional assays and in vivo studies in immunocompetent mouse models to evaluate their effects on tumor growth and antitumor immunity. Integrative multi-omics analyses, including transcriptomics, metabolomics, and mass spectrometry, were performed to elucidate the molecular mechanisms underlying NSUN2-mediated immune evasion. A proteolysis-targeting chimera (PROTAC) system was developed to achieve targeted degradation of NSUN2, and the clinical relevance of NSUN2 expression in predicting immunotherapy responses was assessed using institutional and public datasets. Results: The enzymatically inactive NSUN2 mutant had minimal effects on tumor cell proliferation in vitro but markedly promoted tumor immune evasion in vivo. Multi-omics analyses revealed that NSUN2 induced metabolic reprogramming and elevated succinate levels, which suppressed cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling in tumor-associated macrophages (TAMs), thereby remodeling the tumor immune microenvironment and promoting M2-like TAM infiltration. Mechanistically, NSUN2 interacted with GATA-binding protein 3 (GATA3) through its methyltransferase domain, relieving GATA3-mediated transcriptional repression of succinate-CoA ligase GDP/ADP-forming subunit α and β genes (SUCLG1 and SUCLG2), leading to succinate accumulation. A newly developed NSUN2-targeting PROTAC demonstrated therapeutic efficacy and safety in combination with cancer immunotherapy. Clinically, low NSUN2 expression was associated with improved immunotherapy responses and survival. Conclusions: Taken together, these findings revealed a noncanonical role of NSUN2 in reshaping the tumor immunosuppressive microenvironment, positioning NSUN2 as a pivotal repressor of cancer immunity and a promising immunotherapeutic target.

Endogenous metabolites are a class of bioactive metabolic molecules synthesized endogenously within the organism that mediate core physiological processes, spanning bioactive small-molecule compounds, carbohydrates, nucleotides, and gut microbial metabolites. Serving as the fundamental basis for sustaining normal physiological homeostasis, these metabolites also exert pivotal regulatory effects within the tumor microenvironment, especially during the progression of cancer immune evasion. This review encapsulates the major classifications, biological functions, and underlying mechanisms of endogenous metabolites, with a dedicated focus on dissecting the molecular pathways through which these metabolites either facilitate or suppress tumor immune evasion. Additionally, it delves into the interplay between endogenous metabolites and immune checkpoint blockade therapy, with the ultimate goal of offering innovative research insights and promising therapeutic targets for the advancement of cancer immunotherapy.

Background: The clinicopathological and prognostic features of colorectal cancer (CRC) originating from different locations differ greatly. However, the impact of tumour location on the clinicopathological features and prognosis of patients with colorectal mucinous adenocarcinoma (MAC) remains underexplored. This longitudinal international cohort study aimed to investigate the influence of tumour location on clinicopathological features, recurrence, and survival in patients with MAC. Methods: The clinicopathological data of CRC patients who underwent curative surgery and were pathologically diagnosed with MAC across 23 hospitals in China from 2016 to 2021 were collected. Data from 2016 to 2021 MAC patients in the Surveillance, Epidemiology, and End Results (SEER) database were also collected. The study was approved by the Institutional Review Board of The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital [approval No. YXLL-KY-2024(116)]. Chi-squared analysis, Fisher's exact test, or Kruskal-Wallis analysis of variance (ANOVA) was used to assess differences in categorical variables where appropriate. Kaplan-Meier curves were generated to assess survival, which was compared via log-rank tests. Univariable and multivariable survival analyses with Cox regression models were conducted to identify prognostic factors. Results: A total of 2,646 patients from the SEER cohort and 2,439 patients from the Chinese cohort met the eligibility criteria for inclusion in this study. In the SEER cohort, compared with the right-sided colon (RS) group and the left-sided colon (LS) group, the rectum (RC) group was significantly associated with aggressive histologic features, including a worse N (node) stage (P<0.001 and P=0.02) and tumour-node-metastasis (TNM) stage (P<0.001 and P=0.005). In the Chinese cohort, compared with the LS group, the RC group had a worse N stage (P<0.001) and TNM stage (P<0.001). And compared with the RS group, the LS group was significantly associated with aggressive histologic features. In the SEER cohort, the 3-year overall survival (OS) of patients in the RC group was significantly lower than that of patients in the RS group and the LS group (69.0% vs. 77.8% vs. 76.8%, P<0.001) No significant differences were observed in OS (85.3% vs. 88.7% vs. 90.7%, P=0.06) or disease-free survival (DFS) (81.5% vs. 84.2% vs. 87.5%, P=0.06) among the three groups in the Chinese cohort. Conclusions: This nationwide multicentre retrospective study demonstrated that the clinicopathological features and prognoses of MAC patients differ between patients in Western countries and those in China. In addition, MACs originating from different tumour locations present divergent clinicopathological features and prognostic consequences. These findings provide new evidence for further exploration of the features of MAC, and the tumour location should receive increased attention in the clinical study and treatment of MAC.

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.

Aim To evaluate the value of trans-anal multipoint full-layer puncture biopsy (TMFP) in guiding organ preservation strategies and prognostic stratification for locally advanced rectal cancer (LARC) after neoadjuvant therapy. Method This prospective multicenter study was conducted across four tertiary centers in China. Sixty-one LARC patients after neoadjuvant chemoradiotherapy (± immunotherapy) who underwent in vivo TMFP were enrolled. Primary outcomes were TMFP-guided changes in treatment strategy (Watch-and-Wait, W&W, vs. surgery) and overall survival (OS). Results Among 61 patients, 20 achieved clinical complete response (cCR) and 41 were non-cCR. TMFP results significantly altered treatment decisions in non-cCR patients, with 48.8% (20/41) being TMFP-negative; half of these (10/20) successfully adopted a W&W strategy. The postoperative pCR rate in non-cCR but TMFP-negative patients who underwent surgery was 70% (7/10). TMFP demonstrated superior prognostic stratification compared to cCR: the OS of TMFP-negative patients was significantly better than that of TMFP-positive patients (P = 0.04), whereas no significant difference was found between cCR and non-cCR groups (P = 0.58). Among TMFP-negative patients, no survival difference was observed between the W&W and surgery groups (P = 0.40). The procedure was well-tolerated with a low complication rate. Conclusions TMFP serves as a pivotal clinical decision-making tool that safely expands organ preservation opportunities to a significant subset of non-cCR patients and provides powerful prognostic stratification, outperforming traditional cCR assessment. Integrating TMFP into the post-neoadjuvant workflow optimizes the balance between oncological safety and functional preservation.

AMPK activation enhances the efficacy of anti-PD-L1 therapy by increasing phosphorylation of ChREBP.

Tumor metabolic reprogramming is critical for providing energy to support proliferation and resistance to stress-induced cell death. However, the regulatory mechanisms linking these processes remain incompletely understood. Here, using untargeted metabolomics, we demonstrate that creatine potently induces ferroptosis in colorectal cancer (CRC). Mechanistically, creatine binds extracellular signal-regulated kinase 2 (ERK2), impairing its activation by mitogen-activated protein kinase kinase 1 (MEK1). Inhibiting the creatine transporter SLC6A8 reduces creatine uptake and activates ERK2. Activated ERK2 then binds, phosphorylates ferroptosis suppressor protein 1 (FSP1) at Thr109, and stabilizes it to inhibit ferroptosis. Creatine supplementation suppresses tumor growth, enhances CD8+ T cell infiltration, and sensitizes tumors to anti-programmed cell death protein 1 (PD-1) immunotherapy. Our study identifies ERK2 as a creatine sensor regulating FSP1 stability and ferroptosis resistance, highlighting the therapeutic potential of creatine supplementation in combination cancer immunotherapy.

ChREBP promotes chemokine production and recruits TAMs to induce tumor immune evasion.

Constipation, a prevalent gastrointestinal disorder, affects 10 http://clinicaltrials.gov/ct2/show/NCT05352074 ). Registry identifier: NCT05352074. Registration date: April 3, 2022.

Circular RNAs (circRNAs) are a recently discovered kind of regulatory RNAs that have emerged as critical biomarkers of various types of cancers. Metabolic reprogramming has gradually been identified as a distinct hallmark of cancer cells. The pentose phosphate pathway (PPP) plays an indispensable role in satisfying the bioenergetic and biosynthetic demands of cancer cells. However, little is known about the role of circRNAs and PPP in colorectal cancer (CRC). The novel circ_0003215 was identified at low levels in CRC and was negatively correlated with larger tumor size, higher TNM stage, and lymph node metastasis. The decreased level of circ_0003215 was resulted from the RNA degradation by m6A writer protein YTHDF2. A series of functional assays demonstrated that circ_0003215 inhibited cell proliferation, migration, invasion, and CRC tumor metastasis in vivo and in vitro. Moreover, circ_0003215 regulated the expression of DLG4 via sponging miR-663b, thereby inducing the metabolic reprogramming in CRC. Mechanismly, DLG4 inhibited the PPP through the K48-linked ubiquitination of glucose-6-phosphate dehydrogenase (G6PD). Taken together, we have identified m6A-modified circ_0003215 as a novel regulator of metabolic glucose reprogramming that inhibited the PPP and the malignant phenotype of CRC via the miR-663b/DLG4/G6PD axis.

AMPK-mediated ChREBP phosphorylation inhibits the expression of chemokine and choline metabolism genes or proteins.

The absence of ChREBP inhibits tumorigenesis in immunocompetent mice.

Mesenteric-related internal hernia after left hemicolectomy is rare. However, it can cause serious consequences, including upper gastrointestinal obstruction and acute intestinal necrosis. This study aimed to explore the potential risk factors of symptomatic internal hernia (SIH) after a left hemicolectomy. We retrospectively reviewed the data of patients who underwent a left hemicolectomy at 10 tertiary hospitals between January 2018 and June 2024. Their baseline information, surgical procedures, and early postoperative complications (within 3 months after surgery) were recorded and analyzed. Overall, 468 patients were included in this study, the majority of patients underwent laparoscopic surgery (76.9

Choline induced macrophages to acquire an immunostimulatory phenotype.

Background Intersphincteric resection (ISR) is a procedure aimed at preserving the anus during the treatment of ultra-low rectal cancer (ULRC). However, the absence of an effective predictive model for selectively identifying patients suitable for laparoscopic ISR (LISR) operations persists, primarily owing to factors related to pelvic anatomy. Methods The present study encompassed individuals diagnosed with ULRC, who underwent LISR between January 2017 and August 2022. These ULRC patients were stratified into difficult or non-difficult LISR groups using recognized and widely accepted scoring criteria. Following the identification of crucial variables, five machine learning (ML) models—Logistic Regression (LR), Support Vector Machine (SVM), K-Nearest Neighbors (KNN), Extreme Gradient Boosting (XGBoost), and the Random Forest (RF) algorithm—were employed to predict surgical difficulty for LISR. Ultimately, area Under the Curve (AUC) and other indices were utilized to evaluate the predictive performance of these ML models. Results In adherence to the inclusion and exclusion criteria, finally, 163 patients diagnosed with ULRC were included in the present study. Among these, 36 patients (22.1%) were categorized into the difficult ISR group, while the remaining 127 patients (77.9%) were classified as belonging to the non-difficult ISR group. Using Lasso regression and binary logistic regression analysis, nine variables were selected for constructing the ML model. To enhance the reliability and predictive accuracy of this study, we established two types of ML models, each incorporating either nine variables or all variables, respectively. One category preserved all variables, with RF yielding the best performance (accuracy: 0.878, PPV: 1, NPV: 0.867, sensitivity: 0.4, specificity: 1, AUC: 0.877), while the other category retained the screened 9 variables, with SVM demonstrating superior performance (accuracy: 0.857, PPV: 0.636, NPV: 0.921, sensitivity: 0.7, specificity: 0.897, AUC: 0.854). Conclusions The proposed ML model offers a dependable and precise approach to classify ULRC patients undergoing LISR using preoperative pelvimetry imaging data. These models can assist clinicians in better preparing for challenging ISR cases and optimizing treatment plans for individual ULRC patients.

The limited success of current immunotherapies emphasizes the need for new targets and combination treatments. V-domain Ig suppressor of T cell activation (VISTA) is a promising immune checkpoint target in cancer immunotherapy, but its regulatory mechanism is poorly understood. Through CRISPR knockout screening and proteomic analysis, we identify tripartite motif containing 25 (TRIM25) as a positive regulator for VISTA largely through antagonizing its degradation signaling. Moreover, ERK-mediated phosphorylation of VISTA at Thr284 enhances its interaction with TRIM25, leading to VISTA stabilization. A VISTA-derived phospho-peptide competitively disrupts TRIM25–VISTA interaction, thereby reducing VISTA expression and potentiating the anti-tumor efficacy of PD-1/PD-L1 blockade. Moreover, single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in mice with T cell-specific knockout of Trim25. Of note, genetic ablation of Trim25 in T cells not only improves anti-PD-L1 immunotherapy, but also significantly ameliorates CAR T anti-tumor activity in various mouse tumor models. Collectively, this study unveils a mechanism for VISTA regulation in T cells and highlights targeting TRIM25–VISTA as a potential strategy to enhance tumor immunotherapy.

Hyperexpression of ChREBP is associated with a poor prognosis and “immune deserts” phenotype in CRC.

AIM:Assessing tumour response following neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer is essential for selecting patients for the watch-and-wait procedure. The accuracy of clinical complete response (cCR) for predicting pathological complete response (pCR) is inadequate. The aim of this study was to assess the ability of transanal multipoint full-layer puncture biopsy (TMFP) to predict pCR following nCRT for rectal cancer. METHOD:This nonrandomized prospective multicentre trial enrolled 113 patients from four centres between April 2020 and June 2023. Of these, 63 were assigned to the in vitro TMFP group and 50 to the in vivo TMFP group. The primary outcome measured was the predictive accuracy of TMFP for pCR. RESULTS:All patients underwent total mesorectal excision. TMFP showed significantly higher accuracy for predicting pCR than cCR (87.6% vs. 68.1%, p = 0.016). The positive predictive value was higher for in vivo than for in vitro TMFP (90.0% vs. 64.5%, p = 0.018), and the predictive accuracy did not differ significantly between the two groups (94.0% vs. 82.5%, p = 0.066). In cCR patients, although with no significant difference between in vivo and in vitro TMFP regarding positive predictive value (95.0% vs. 86.7%, p = 0.794) and accuracy (96.0% vs. 92.9%, p = 1.000), the predictive accuracy of in vivo TMFP was as high as 96%. CONCLUSIONS:TMFP is safe and feasible for assessing the response of rectal cancer to nCRT. TMFP showed high sensitivity and accuracy for predicting pCR and could be a useful supplement to the current cCR standard.

LPIN3 has emerged as a key factor in a variety of malignancies, although its precise role in colorectal cancer (CRC) remains unclear. By analyzing the data from The Cancer Genome Atlas, we discovered that the expression pattern of LPIN3 and the relevant makeup of the immune microenvironment were immensely diverse among tumors. LPIN3 is abundantly expressed in CRC and may enhance tumor growth by activating the β-catenin signaling pathway. In addition, we discovered that LPIN3 might reduce tumor antigen presentation signals, hence suppressing CD8+ T cell-mediated cytotoxicity. Furthermore, high expression of LPIN3 predicts decreased CD8+ T cell infiltration and effector function via bioinformatics analysis. Indeed, CD8+ T cell-mediated cytotoxicity as well as CD8+ T cell infiltration and activation in vivo were strengthened by LPIN3 knockdown. To sum up, our results highlight the part that LPIN3 plays in driving the progression of CRC by regulating β-catenin signaling and CD8+ T cell activity.