Discovery of o-aminodiphenyl-based USP7 inhibitor for immune activation and antitumor response in colorectal cancer.

CD47-targeted liposomal chemotherapy upregulates CD47 expression and induces microsatellite instability which enhances cancer immunotherapy.

Dual-sensitization nanoformulation combining glutamine metabolism inhibition and Fas/FasL activation for enhanced colorectal cancer immunotherapy.

Enhancement of antitumor immunity by CTLA-4 antisense oligonucleotides with CpG motif in mice.

Colorectal cancer (CRC) is among the most prevalent malignancies. However, the regulatory networks involved in tumor occurrence and development are still poorly understood. Human endogenous retroviruses (HERVs), a class of transposable elements, have been implicated in the development and progression of various human cancers. This study presents the first comprehensive locus-specific profiling of the expression of HERV gene transcripts in rectal cancer, revealing significantly dysregulated HERVs. Analysis of data from three Gene Expression Omnibus data sets revealed 25 upregulated HERVs and 7 downregulated HERVs. Dysregulation of HERV6196, a type of HERVH, was validated through reverse transcription quantitative PCR and droplet digital PCR in cells and tissues. Additionally, HERV6196 promoted the proliferation, inhibited the apoptosis, enhanced the colony formation ability, and enhanced the migration capability of rectal cancer cells. Moreover, HERV6196 functioned as an enhancer, promoting the expression of neighboring genes and the development of CRC. In summary, the present results revealed that HERV6196 is involved in the pathogenesis of rectal cancer, indicating the potential contribution of dysregulated HERVs to the development and progression of CRC through gene expression modulation.IMPORTANCEThe role of human endogenous retroviruses (HERVs) in colorectal cancer (CRC) remains insufficiently understood. The present study revealed aberrant expression of HERV gene transcripts in cancerous tissues compared with non-cancerous tissues. HERV6196 contributes to CRC progression by regulating the expression of neighboring genes. These findings suggest that HERVs may serve as enhancers and regulate oncogenic gene expression, providing new insights for rewiring transcriptional regulatory networks in CRC pathogenesis.

Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, with tumor immune evasion posing a major challenge to effective immunotherapy. Post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, methylation, and glycosylation, are critical regulators of protein function and stability, profoundly influencing tumor immunogenicity and the tumor immune microenvironment. This review comprehensively examines how PTMs modulate key immune processes in CRC, such as antigen presentation, immune cell infiltration, and immune checkpoint regulation. We discuss PTM-mediated mechanisms that shape T cell exhaustion, macrophage polarization, and immunosuppressive cytokine networks within the tumor microenvironment. Moreover, we highlight the impact of PTMs on therapeutic response and resistance to immune checkpoint blockade and adoptive cell therapies. Emphasis is placed on emerging PTM-targeted strategies to enhance antitumor immunity and overcome immunotherapy resistance. Finally, we explore advances in multi-omics technologies and proteomic profiling that promise to accelerate the identification of PTM biomarkers and novel therapeutic targets. By integrating mechanistic insights with translational perspectives, this review aims to provide a foundation for leveraging PTMs to optimize immunotherapeutic approaches in colorectal cancer.

Colorectal cancer (CRC) is a leading cause of global cancer-related mortality and morbidity, with rising incidence in Sub-Saharan African countries over the past decade. This study aims to determine the prevalence, and describe location, as well as histopathology of polyps in patients undergoing colonoscopy in Ghana. The prevalence and polyp characteristics provide additional data and have implications for developing locally relevant screening guidelines. Retrospective chart review of patients ≥18 years who completed a colonoscopy at the anonymized from 1 January 2021 to 31 December 2023. 510 patients were included in the analysis. The mean age was 54.8(±0.7 SD); 62% were males. Abnormal findings included hemorrhoids (47.1%), polyps (30.0%), diverticular disease (10.2%), and colonic mass (2.4%). Overall adenoma detection rate (ADR) was 26.1%. Histopathology showed 30.8% tubular adenoma, 30.1% hyperplastic polyps, and 16.0% tubulovillous adenoma. The highest burden of polyps was in the 60 to 80-year-old age group. The prevalence of CRC was 2.2% in our study. CRC prevalence rates remain relatively low in Sub-Saharan Africa. Access to screening is limited, and the numbers may be underestimated. A cost-effective screening strategy to improve early detection and outcomes is needed.

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths globally, primarily due to treatment failure associated with metastasis and recurrence driven by chemoresistant cancer stem-like cells (CSCs). Annexin A1 (Anx-A1) is implicated in regulating apoptosis and autophagy, two crucial mechanisms contributing to chemoresistance. However, the precise role of Anx-A1 in modulating these mechanisms in CRC CSCs, specifically via the PI3K/AKT/mTOR pathway, is not well understood. This study aimed to explore the role of Anx-A1 in modulating apoptosis-autophagy interplay in a 5-FU-resistant colorectal CSC model using HCT 116, particularly through its regulatory effects on the PI3K/AKT/mTOR signaling pathway. A 5-FU-resistant CRC CSC model was developed by sequentially exposing HCT 116 cells to 5-fluorouracil (5-FU). The model was characterized by assessing CSC markers (CD133, ALDH1, ABCG2, Oct-3/4) via flow cytometry and Simple Western analysis. Anx-A1 knockdown and overexpression were performed using siRNA and expression plasmids, respectively. Chemosensitivity was evaluated through cell viability assays, while apoptosis and autophagy markers were assessed by caspase assays, proteome profiler arrays, Western blotting, and autophagy flux analysis. The expression levels of PI3K, p-PI3K, AKT, p-AKT, and mTOR were quantified using Simple Western analysis. The 5-FU-resistant HCT 116 demonstrated significantly elevated IC50 values, heightened expression of CSC markers, and increased Anx-A1 expression. Knockdown of Anx-A1 markedly enhanced chemosensitivity, significantly reduced cell viability, and modulated CSC marker expression. Anx-A1 knockdown led to mild induction of apoptosis characterized by increased caspase activity, concurrent downregulation of multiple apoptotic proteins, and substantial autophagy induction demonstrated by increased LC3-II and p62 expression, and enhanced autophagosome degradation. Analysis of the PI3K/AKT/mTOR pathway revealed that Anx-A1 knockdown significantly increased phosphorylated PI3K p85α and AKT1/2/3, and substantially downregulated mTOR, illustrating the dynamic regulation of apoptosis-autophagy interplay. Anx-A1 modulates 5-FU induced-chemoresistance in colorectal CSCs by orchestrating the apoptosis-autophagy balance through the PI3K/AKT/mTOR pathway. Targeting Anx-A1 provides a promising therapeutic strategy to enhance chemosensitivity and overcome resistance in CRC treatment.

Colorectal signet ring cell carcinoma (SRCC) is a rare and aggressive subtype with a high propensity for peritoneal metastasis, yet the underlying mechanisms remain poorly understood. We isolated cancer-associated adipocytes (CAAs) from omental tissue adjacent to SRCC peritoneal metastases and examined their morphological and metabolic features compared to normal adipocytes (NAs). Co-culture systems, patient-derived organoids (PDOs), transcriptomic/metabolomic profiling, and peritoneal metastasis mouse models were employed to assess the functional impact of CAAs. The role of fatty acid binding protein 4 (FABP4) and its regulation via CAA-derived exosomes was also investigated. CAAs exhibited a dedifferentiated phenotype, enhanced free fatty acid secretion, and upregulation of matrix metalloproteinases. Co-culture with CAAs significantly promoted SRCC PDO proliferation, stemness, and peritoneal metastasis, accompanied by a metabolic shift toward fatty acid utilization. Among fatty acid metabolism-related genes, FABP4 was markedly upregulated in peritoneal metastases and associated with poor prognosis. Functional assays confirmed that FABP4 promoted fatty acid oxidation (FAO), stemness, and metastasis in PDOs, while FABP4 knockdown abrogated these effects. Mechanistically, CAA-derived exosomes induced FABP4 expression in PDOs, and inhibition of exosome release reversed the pro-tumorigenic phenotypes. CAA-derived exosomal signaling promotes SRCC aggressiveness through FABP4-mediated fatty acid metabolic reprogramming, identifying FABP4 as a potential therapeutic target for peritoneal metastasis in colorectal SRCC.

In response to rising colorectal cancer (CRC) incidence in younger adults, the US Preventive Services Task Force now recommends CRC screening to begin at age 45. Despite this change, screening rates remain low among 45- to 49-year-olds. Mailed fecal immunochemical test (FIT) programs with navigation have shown promise in increasing uptake. To evaluate the effectiveness of a mailed FIT program with culturally tailored navigation to improve CRC screening rates among adults aged 45-49 in a large, hospital-based safety-net primary care clinic. A quality improvement initiative identified eligible patients aged 45-49 not up to date with CRC screening. FIT kits were mailed following an invitation letter in English and Spanish with messaging based on the health belief model. Navigation was multi-modal including tailored patient education, bilingual phone calls, and reminder letters. Screening completion and follow-up outcomes were tracked via Epic and REDCap. Of the 589 patients who received mailed FITs, 143 (24%) returned a completed test. Overall, Hispanic patients returned FITs at higher rates than non-Hispanic patients (29% vs. 21%), including both those who received navigation and those who did not. Navigation improved return rates, with 16% of outstanding FITs returned after outreach. Eleven tests were positive (8%), and 8 (73%) had a follow-up colonoscopy which identified 3 advanced adenomas. A culturally tailored mailed FIT intervention with navigation significantly improved screening rates among newly eligible adults, especially Hispanic patients. The findings highlight the importance of culturally tailored, multi-modal navigation to increase screening among younger, newly eligible adults and reduce screening disparities among underrepresented groups. Findings support broader implementation and suggest that navigation services can advance health equity in primary care. Future work should explore scalability and compare navigation to usual care.

Metachronous cancer risk varies by mismatch repair mutation in patients with hereditary nonpolyposis colorectal cancer. Total colectomy offers decreased risk of metachronous colorectal cancers but decreased quality of life compared with segmental colectomy. Compare segmental versus total colectomy for colon cancer via a mutation-specific Markov decision model. Simulated survival and colorectal metachronous occurrence among patients with MLH1, MSH2, or MSH6 mutations undergoing either segmental or total colectomy. National databases, literature review. Simulated patients with hereditary nonpolyposis colorectal cancer. Overall survival, quality-adjusted life years based on procedure-specific utility states (segmental colectomy 0.99, total colectomy 0.95). Among patients aged 25, total colectomy offered less than one year of increased mean survival compared with segmental resection across all mutations (MLH1: 0.8 years, MSH2: 0.9, MSH6: 0.3). This difference in survival decreased with increasing age. Segmental resection offered a small increase in quality-adjusted life years compared with total colectomy across all ages. This difference was highest for MSH6 (0.9 years vs. MLH1: 0.6 and MSH2: 0.4 at age 25), particularly at younger ages of diagnosis. In a sensitivity analysis, lower total colectomy utility states resulted in greater increases in quality-adjusted life years with segmental colectomy across all mutations. Metachronous cancer risk data does not distinguish between colon and rectal cancers and is extrapolated beyond age 70. Segmental and total colectomy offer similar survival and quality-adjusted life year outcomes. With decreased risk of metachronous cancers, patients with MSH6 mutations across all ages may prefer segmental resection due to higher quality-adjusted life years and lower survival benefits from total colectomy compared with MLH1 and MSH2 patients. Operative strategy in patients with hereditary nonpolyposis colorectal cancer should be individualized, and this study shows that mutation-specific differences in survival and quality-adjusted life years are small. See Video Abstract.

Longitudinal data are often available in cohort studies and clinical settings, such as covariates collected at cohort follow-up visits or prescriptions captured in electronic health records. Such longitudinal information, if correlates with the health event of interest, may be incorporated to dynamically predict the probability of a health event with better precision. Landmarking is a popular approach to dynamic prediction. There are well-established methods for landmarking using full cohort data, but collecting data on all cohort members may not be feasible when resource is limited. Instead, one may select a subset of the cohort using subsampling designs, and only collect data on this subset. In this work, we present conditional likelihood and inverse-probability weighted methods for landmarking using data from cohort subsampling designs, and discuss considerations for choosing a particular method. Simulations are conducted to evaluate the applicability of the methods and their predictive performance in different scenarios. Results show that our methods have similar predictive performance to the full cohort analysis but only use small fractions of the full cohort data. We use real nested case-control data from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial to illustrate the methods.

Survival outcomes of ERBB2-amplified metastatic colorectal cancer treated with first-line chemotherapy

Colorectal surgery for familial adenomatous polyposis requires a balance between minimizing cancer risk, surgical risk, and quality-of-life preservation. Options include total colectomy/ileorectal anastomosis or proctocolectomy/ileal pouch-anal anastomosis. Prior studies comparing short-term postoperative outcomes are dated and mainly include laparotomies. Minimally invasive surgery is common in current practice, but there are no contemporary studies comparing postoperative outcomes between the 2 surgeries. This study investigated postoperative outcomes including leak, obstruction, and surgical site infection after ileorectal anastomosis versus ileal pouch-anal anastomosis in familial adenomatous polyposis. This was a retrospective, observational cohort study. This study was conducted at a single academic institution using a prospectively maintained hereditary colorectal cancer syndrome database from 2008-2023. Patients with familial adenomatous polyposis who underwent index ileorectal anastomosis or ileal pouch-anal anastomosis during the study period and met inclusion criteria were selected. Main outcome measures include development of a postoperative complication, readmission, and reoperation within 30 and 90 days. A total of 217 patients were included - 146 (67.3%) with ileorectal anastomosis and 71 (31.7%) with ileal pouch-anal anastomosis. 85.3% had minimally invasive surgery and 14.7% had open surgery. 87.3% of ileal pouch-anal anastomosis patients had an ileostomy. No significant difference in the number of patients who developed a 30 or 90-day complication was observed. The most common 90-day complication was ileus (34.2% vs 21.2%) and most common 90-day severe complication was anastomotic leak (4.8% vs 7.0%). Patients had a higher frequency of readmission and reoperation after ileal pouch-anal anastomosis (13.0% vs 33.8% and 6.8% vs 18.3%, respectively). This study is limited by its retrospective nature and short follow-up time. In the modern era, with most surgeries being done minimally invasively, and the majority of ileal pouch-anal anastomosis patients being diverted, surgeries are safe. Severe complications are uncommon and similar between groups. See Video Abstract.

Glutamine metabolism is crucial for sustaining tumor cell viability and growth, broadly promoting prospects for the therapeutic targeting of glutamine dependence. However, further research is needed to address key translational issues, particularly to better understand the adaptive survival responses employed by cancer cells in overcoming nutrient deficiency. Long-chain acyl-CoA synthetase 5 (ACSL5) is found to be upregulated under glutamine deprivation, acting to sustain tumor cell viability by enhancing both glycolytic flux and oxidative phosphorylation. ACSL5 operates within a p53 regulatory loop: p53 transcriptionally upregulates ACSL5, while ACSL5 competes with MIB1 to stabilize MDM2, suppressing p53 expression. Mechanistically, ACSL5 relieves p53-mediated inhibition of PGAM1 to drive glycolysis, while its mitochondrial localization promotes IDH2 activation to accelerate the TCA cycle. Nonetheless, these metabolic increases also generate reactive oxygen species (ROS), inducing DNA damage and significantly enhancing colorectal cancer cell sensitivity to oxaliplatin. The latter provides an explanation as to why colorectal tumors with high ACSL5 expression display preferentially improved patient outcomes from chemotherapy. Collectively, the findings reveal a new pathway for non-genetic chemotherapy resistance mechanisms, deepen the understanding of metabolic reprogramming in tumor cells, and offer potential therapeutic targets for future treatment strategies.

Leptin as a Biomarker of Cancer Prognosis: A Friend of Colorectal Cancer

ColoNet: A CNN-Based System for Early Diagnosis and Classification of Colon Adenocarcinoma in Digital Histopathology

Lactylation, a recently discovered post-translational modification, has emerged as a critical regulator in cancer biology. Although chemotherapy remains the first-line treatment for metastatic colorectal cancer (CRC), only a subset of patients responds to it. This study aimed to identify key lactylation-related genes in CRC and evaluate their potential as predictive biomarkers for chemotherapy response. Gene expression profiles and corresponding clinical data from CRC patients were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases. Differentially expressed genes (DEGs) were identified using the limma R package, and key modules were selected through weighted gene co-expression network analysis (WGCNA). Intersecting genes were determined by aligning DEGs with WGCNA module genes. A predictive model was developed utilizing 11 machine learning algorithms and 92 algorithm combinations. Furthermore, the correlation between lactylation-related gene score and immune infiltration as well as drug sensitivity in CRC were also investigated with "CIBERSORT" and "oncoPredict" package. Eight lactylation-related genes in CRC were identified and used to construct a predictive model employing Random Forest (RF) and Gradient Boosting Machine (GBM) algorithms. The model demonstrated strong predictive efficacy for chemotherapy response in CRC patients. Using lactylation gene scores, we effectively stratified patients into high- and low-score groups, which showed distinct patterns in immune cell infiltration, tumor mutational profile, and response to conventional antitumor drugs. Notably, the high-lactylation score group exhibited reduced Treg immune characteristics and increased sensitivity to 5-Fluorouracil. In summary, our findings demonstrate that machine learning-driven analysis of lactylation biomarkers represents a promising approach for advancing personalized therapy and optimizing clinical management in CRC.

Comment on “A SEER‐Based Analysis of Survival Predictors in Stage I Colorectal Cancer”

Clinical Significance of Lactate Dehydrogenase A Expression in Colorectal Cancer