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.

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

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

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.

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by complex aetiological factors and extensive extraintestinal manifestations. Anxiety and depression, which are common mental disorders, have shown increasing incidence rates in recent years. Compared with the general population, IBD patients are more susceptible to anxiety and depression, which consequently exacerbate the disease burden and increases the risk of adverse clinical outcomes. Emerging evidence reveals shared pathophysiological mechanisms between IBD and anxiety and depression. This review rigorously focuses on anxiety and depression in IBD, distinguishing these conditions from primary anxiety or depressive disorders, as well as from mood disturbances secondary to other chronic illnesses, and summarizes the latest research literature highlighting their unique comorbid characteristics. Firstly, we integrate recent epidemiological evidence to establish their bidirectional relationship. Subsequently, we summarize the comorbid mechanisms as follows: genetic predisposition, impaired hippocampal neurogenesis, specific brain region alterations, gut microbiota dysbiosis, hypothalamic‒pituitary‒adrenal (HPA) axis dysregulation and neuroimmune interactions mediated by inflammatory cytokines and neurotransmitters. Finally, we explore novel therapeutic approaches derived from these mechanistic insights, aiming to enhance clinical recognition of this bidirectional comorbidity and optimize the management of such comorbid conditions.

Introduction Copy number variation is a significant characteristic of colorectal cancer progression. RBFOX1 (A2BP1) is the gene with the highest frequency of copy number loss in colorectal cancer, but current research related to it and colorectal cancer is relatively scarce. Methods Data from TCGA and other sources were used to analyze the copy number variation and mRNA expression levels of RBFOX1, as well as their correlation with clinical pathological data. Immunohistochemistry and immunofluorescence experiments were used to analyze the expression of RBFOX1 protein in colorectal cancer cells and tissues. Results RBFOX1 has a high frequency (22.4%) of copy number loss and diverse copy number variations in colorectal cancer tissues. High-level RBFOX1 deletion is prone to occur in the right-sided colon and tissues with high microsatellite instability. The copy number variation of RBFOX1 and mRNA expression are not correlated. In tumor tissues, RBFOX1 mRNA shows a characteristic of reduced expression, which is significantly related to BRAF mutation (P = 4.7e-05, P = 0.03). Low expression of RBFOX1 is prone to occur in the right-sided colon and tissues with high microsatellite instability. The protein encoded by RBFOX1 is expressed in normal intestinal tissues, but shows a characteristic of absence in some colorectal cancer tissues. Conclusion In the right-sided colon and tissues with high microsatellite instability, RBFOX1 shows copy number loss and low mRNA expression. This characteristic is closely related to BRAF gene mutation, and the protein of RBFOX1 is absent in some colorectal cancer tissues.

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.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder that often has extraintestinal manifestations. Anxiety and depression are common in patients with IBD. Recent studies have demonstrated that the hippocampus contributes to the pathogenesis of psychiatric comorbidities in IBD. Therefore, this study aimed to elucidate the cellular and molecular changes in the hippocampus before and after the induction of colitis through single-nucleus sequencing technology, thus providing insights into the comorbidity mechanisms. Colitis mouse models were established by adding dextran sulfate sodium (DSS) to the drinking water. Behavioral tests were used to evaluate anxiety- and depression-like behaviors. Single-nucleus RNA sequencing analysis was carried out to identify specific neuronal subpopulations in the hippocampal and their functions. We found that DSS-treated mice exhibited intestinal inflammation and anxiety- and depression-like behaviors. The number of cells in the DG cluster and the Meis2 cluster decreased significantly after DSS treatment. Further analyses revealed that the DG-2 cluster might represent a key hippocampal subpopulation mediating the association between IBD and anxiety/depression. This study provides novel insights into the role of neuronal cells in the pathology of the comorbidity. Neurons of the DG-2 subpopulation may serve as a potential target for future therapeutic interventions.

ChREBP interacts with SP1 to promote the expression of chemokine and choline metabolism genes.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder that often has extraintestinal manifestations. Anxiety and depression are common in patients with IBD. Recent studies have demonstrated that the hippocampus contributes to the pathogenesis of psychiatric comorbidities in IBD. Therefore, this study aimed to elucidate the cellular and molecular changes in the hippocampus before and after the induction of colitis through single-nucleus sequencing technology, thus providing insights into the comorbidity mechanisms. Colitis mouse models were established by adding dextran sulfate sodium (DSS) to the drinking water. Behavioral tests were used to evaluate anxiety- and depression-like behaviors. Single-nucleus RNA sequencing analysis was carried out to identify specific neuronal subpopulations in the hippocampal and their functions. We found that DSS-treated mice exhibited intestinal inflammation and anxiety- and depression-like behaviors. The number of cells in the DG cluster and the Meis2 cluster decreased significantly after DSS treatment. Further analyses revealed that the DG-2 cluster might represent a key hippocampal subpopulation mediating the association between IBD and anxiety/depression. This study provides novel insights into the role of neuronal cells in the pathology of the comorbidity. Neurons of the DG-2 subpopulation may serve as a potential target for future therapeutic interventions.

The differential metabolites identified by LC-MS from shChrebp or shNC MC38 tumors.

Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy response. Aberrant choline metabolism is emerging as a defining hallmark of cancer. In this study, we found that carbohydrate-responsive element-binding protein (ChREBP)-mediated choline deprivation induced tumor-associated macrophage (TAM) reprogramming and maintained an immunosuppressive tumor microenvironment. Mechanistically, ChREBP interacted with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CCL7 and choline transporter SLC44A1. As such, high CCL2 and CCL7 expression promoted recruitment of TAMs. Tumor cells with high SLC44A1 levels competed with M1-like TAMs for choline, inhibiting cGAS/STING signaling and promoting the repolarization of M1-like to M2-like macrophages. Clinically, ChREBP-SP1-choline metabolism axis expression was associated with poor clinical outcome in colorectal cancer. Thus, the study identified the interplay between tumors and TAMs via choline competition as a previously unknown immune evasion mechanism in the tumor microenvironment and proposes ChREBP as a potential immunotherapeutic target in cancer.Significance: ChREBP induces a choline-deprived tumor microenvironment and promotes chemokine secretion to facilitate immune evasion, suggesting targeting ChREBP as a therapeutic approach to improve the efficacy of immunotherapy.

Tumor cell ChREBP-mediated choline deprivation orchestrates TAMs reprogramming and immune evasion.