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Advancements in the Treatment of Colorectal Cancer

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: 30 September 2026 | Viewed by 14231

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Prof. Dr. Andee Dzulkarnaen Zakaria

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Guest Editor

Department of Surgery, School of Medical Science & Hospital Universiti Sains Malaysia, Kota Bharu, Kelantan, Malaysia
Interests: colorectal cancer; advanced colorectal surgery; advanced nutritional support; perineal disease; ERAS; advanced endoscopy

Special Issue Information

Dear Colleagues,

This Special Issue spotlights advances transforming colorectal cancer (CRC) care—from prevention to survivorship—through precision and personalized medicine. Enhanced screening, risk stratification, and genomic profiling enable biomarker-driven treatment selection, while AI augments imaging, pathology, and real-time decision support. In metastatic CRC, multidisciplinary care integrates metastasectomy, ablative techniques, stereotactic radiotherapy, hepatic–arterial infusion, and advanced chemotherapy combinations tailored by tumor biology.

Translational breakthroughs include liquid biopsy, proteomics profiling, and circulating tumor DNA for minimal residual disease monitoring, resistance mapping, and dynamic therapy adaptation. The issue examines differential biology of right- versus left-sided tumors, sequencing of perioperative therapy, and the evolving roles of targeted agents (RAS/BRAF/HER2 and KRAS G12C) and immunotherapy in MSI-H/dMMR disease. Across the continuum, precision medicine frameworks align with personalized care to mitigate toxicity, enhance quality of life, and address health equity. Collectively, these studies define next-generation, data-driven standards poised to elevate CRC outcomes. All in all, ‘From lab evidence to clinical practices’.

Prof. Dr. Andee Dzulkarnaen Zakaria
Guest Editor

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Keywords

genomic profiling
advanced nutritional support
AI
MDT
adjuvant therapy

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Published Papers (8 papers)

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Research

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16 pages, 682 KB

Open AccessArticle

Validation of Multi-Target Stool DNA Methylation Test for Colorectal Cancer Detection: A Preliminary Analysis

by Khairul Anwar Abdul Rahman, Nabil Mohammad Azmi, Shahrun Niza Abdullah Suhaimi, Zairul Azwan Mohd Azman, Farhana Raduan, Khairul Najmi Muhammad Nawawi, Shamsul Azhar Shah, Geok Chin Tan, Yin Ping Wong and Sayyidi Hamzi Abdul Raub

Biomedicines 2026, 14(5), 999; https://doi.org/10.3390/biomedicines14050999 - 27 Apr 2026

Viewed by 2152

Abstract

Colorectal cancer (CRC) develops gradually from precancerous adenomas and is highly curable when detected early. In Malaysia, however, most cases are diagnosed at advanced stages, leading to poorer outcomes despite the availability of screening programmes such as the immunological Faecal Occult Blood Test (iFOBT). Limited screening uptake and poor adherence contribute to delayed diagnosis. Therefore, effective non-invasive and patient-friendly screening tools are essential. Background/Objectives: This study aims to validate the diagnostic performance of the multi-target stool DNA (mt-sDNA) test. Methods: This cross-sectional validation study was conducted at the Endoscopic Center, Hospital Canselor Tuanku Muhriz (HCTM), from January 2024 to September 2025. Adults aged 18–75 years undergoing elective or emergency colonoscopy were included. Results: Among 246 patients, most were male (56.5%), Malay (65.2%), and aged 55–75 years (91.3%). CRC prevalence was 8.5%. A significant association was observed between age group and colonoscopy findings (p = 0.005), with older individuals more likely to have CRC or adenomatous lesions. Most CRC (90.4%) and advanced adenoma (84.6%) cases occurred in symptomatic patients; however, this difference did not demonstrate a significant association with colonoscopy outcomes (p = 0.069). Per rectal bleeding, constitutional symptoms, altered bowel habit, abdominal pain and constipation were significantly associated with CRC and adenomatous lesions. The mt-sDNA test showed a sensitivity of 63.2%, specificity of 85.0%, positive predictive value of 36.4%, and negative predictive value of 94.4%. Conclusions: Preliminary findings indicate that mt-sDNA demonstrates good specificity and high negative predictive value, but moderate sensitivity and low positive predictive value. Full article

(This article belongs to the Special Issue Advancements in the Treatment of Colorectal Cancer)

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17 pages, 1076 KB

Open AccessArticle

Skeletal Muscle Gauge and Complementary Pan-Immune-Inflammation Value for Risk Stratification of 30-Day Major Complications After Colorectal Cancer Surgery

by Botond-István Kiss, Daniela Tatiana Sala, Renáta Moriczi, Szabolcs-Attila Gábor, Árpád Török, Gabriel-Mircea Muresan, Tivadar Bara, Jr., Márton István Dénes, Szilárd-Leó Kiss, Sr., Szilárd-Leó Kiss, Jr., Orsolya Kiss-Toth and Radu-Mircea Neagoe

Biomedicines 2026, 14(4), 894; https://doi.org/10.3390/biomedicines14040894 - 15 Apr 2026

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Abstract

Background: Major morbidity and mortality remain important concerns after colorectal cancer (CRC) surgery. Cancer-related sarcopenia and heightened systemic inflammation may increase the risk of early postoperative major complications. Methods: In this retrospective single-center study, we analyzed 190 patients undergoing major CRC surgery. Skeletal muscle gauge (SMG) and the pan-immune-inflammation value (PIV) were assessed as preoperative risk markers, and 30-day major complications were evaluated. Results: Low SMG was strongly associated with major complications (OR 6.50, 95% CI 3.24–13.05; p < 0.001), and high PIV was also associated with increased risk (OR 3.51, 95% CI 1.77–6.99; p < 0.001). In multivariable analysis adjusting for age, surgical urgency, and procedure type, low SMG and emergency surgery remained independent predictors of 30-day major complications. The highest-risk phenotype (high PIV/low SMG; n = 23) had a major complication rate of 78.3% (18/23) (p < 0.001). A clinical model including age, urgency, and procedure type yielded an AUC of 0.739 (95% CI 0.661–0.816). Adding low SMG improved discrimination (AUC 0.784, 95% CI 0.711–0.857), with only a small additional increase after adding high PIV (AUC 0.791, 95% CI 0.717–0.864). Conclusions: Preoperative low SMG was independently associated with 30-day major complications after CRC surgery, while PIV provided complementary risk-stratification value. The combined high-PIV/low-SMG phenotype identified patients with particularly high postoperative risk. Full article

(This article belongs to the Special Issue Advancements in the Treatment of Colorectal Cancer)

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16 pages, 10875 KB

Open AccessArticle

RPS6KA1 Remodels Fatty Acid Metabolism and Suppresses Malignant Progression in Colorectal Cancer

by Qixin Liu and Ziheng Peng

Biomedicines 2026, 14(2), 374; https://doi.org/10.3390/biomedicines14020374 - 5 Feb 2026

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Abstract

Background: Colorectal cancer (CRC), with high incidence but low rates of early diagnosis, poses significant challenges to public health worldwide. Lipid metabolic reprogramming has been closely associated with CRC occurrence and development. This study aimed to identify key fatty acid metabolism-related molecules involved in the development of CRC and to explore potential prognostic biomarkers and therapeutic targets. Methods: Based on The Cancer Genome Atlas (TCGA) data from colon adenocarcinoma (COAD) patients, we applied weighted gene co-expression network analysis (WGCNA), Cox regression, and least absolute shrinkage and selection operator (LASSO) to identify fatty acid metabolism-related signature genes in CRC. Expression validation and prognostic analysis were conducted. Summary-data-based Mendelian randomization (SMR) was used to infer causal relationships between target genes and CRC. Single-cell transcriptomics and immune infiltration analysis elucidated underlying pathogenic mechanisms. Cellular and animal experiments validated tumor-suppressive effects and lipid metabolic regulatory mechanisms. Results: RPS6KA1 and CHGA were identified as fatty acid metabolism-related signature genes in COAD. Only RPS6KA1 was significantly downregulated in COAD and negatively correlated with poor prognosis (p = 0.0069). SMR confirmed its tumor-suppressive role, potentially associated with enhanced antitumor functions of CD8⁺T cells and follicular helper T cells. In vitro and in vivo experiments demonstrated that RPS6KA1 inhibits malignant progression of colon cancer and modulates fatty acid metabolism. Conclusions: Integrated multi-dimensional bioinformatic and experimental analyses reveal that RPS6KA1 remodels fatty acid metabolism and suppresses malignant progression, indicating its value as a prognostic biomarker in CRC and providing new insights for therapeutic strategies. Full article

(This article belongs to the Special Issue Advancements in the Treatment of Colorectal Cancer)

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20 pages, 9472 KB

Open AccessArticle

Single-Cell Analysis Reveals Epithelial Heterogeneity and Tumor Microenvironment Characteristics During the Malignant Progression of Colorectal Cancer

by Qianqian Chen, Yaoqian Yuan, Shuai Tian, Jiayan Zhou, Kunming Lv and Enqiang Linghu

Biomedicines 2026, 14(2), 371; https://doi.org/10.3390/biomedicines14020371 - 5 Feb 2026

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Abstract

Background/Objectives: To mine single-cell sequencing data for colorectal cancer (CRC), identify CRC epithelial cell subtypes, and explore the heterogeneity of epithelial cells and their impact on the tumor microenvironment (TME). Methods: The GSE201348 dataset, including normal, colorectal adenoma, high-grade colorectal intraepithelial neoplasia, and CRC tumor tissue samples, was downloaded from the Gene Expression Omnibus. The Seurat package of R software was used for data quality control, data integration, normalization, and clustering. The Feature Plot and the Recode function were executed to annotate and group the epithelial cells. Finally, genetic differences, copy number variant heterogeneity, pseudotime, cell–cell communication, and Gene Set Variation Analysis (GSVA) were further conducted. Results: In total, 26,335 gene matrices from 263,872 cells were obtained for subsequent analyses. Four cell clusters, including immune cells, fibroblasts, endothelial cells, and epithelial cells, were identified. Epithelial cells were further divided into 11 subgroups characterized by MKI67, SLC27A6, PLCE1, NKD1, KCNMA1, GDA, CLCA4, BEST4, LRMP, ACTG2, and ASPM. GSVA enrichment analysis suggested a role of the “P53 pathway,” “Wnt–β-catenin signaling,” and “MYC targets V1” pathways in epithelial cells during the malignant progression of tumors. Survival analysis indicated that downregulation of KCNMA1 and upregulation of MKI67 were associated with poor prognosis. Cell–cell communication analysis suggested a bidirectional regulatory role between epithelial and fibroblast subsets. Conclusions: This study analyzed the gene expression characteristics of 11 types of epithelial cells during the malignant progression of CRC. KCNMA1⁺ and MKI67⁺ epithelial subpopulations are important indicators for the malignant progression of CRC. Full article

(This article belongs to the Special Issue Advancements in the Treatment of Colorectal Cancer)

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17 pages, 1384 KB

Open AccessArticle

Potential Impact of Microbial Dysbiosis and Tryptophan Metabolites in Advanced Stages of Colorectal Cancer

by Anne Hulin, Aline Rifflet, Florence Castelli, Quentin Giai Gianetto, François Fenaille, Abdel Aissat, Mariette Matondo, Soraya Fellahi, Christophe Tournigand, Christophe Junot, Philippe Sansonetti, Ivo Gomperts-Boneca, Denis Mestivier and Iradj Sobhani

Biomedicines 2026, 14(1), 26; https://doi.org/10.3390/biomedicines14010026 - 22 Dec 2025

Cited by 2 | Viewed by 1064

Abstract

Background/Objectives: We conducted an untargeted metabolomic study in serum, urine, and fecal water in colorectal cancer (CRC) patients compared to healthy controls. The aim was to define the interactions between metabolites and microbiota. Methods: Effluents were collected before colonoscopy. Metabolites were analyzed using LC-HRMS. Bioinformatics analyses included Limma test, along with spectral house and public databases for annotations. Whole-genome shotgun sequencing was performed on fecal samples. Species–metabolite interactions were calculated using Spearman correlation. Interleukins and inflammatory proteins were measured. Results: Fifty-three patients (11 stage I, 10 stage II, 10 stage III, and 22 stage IV) and twenty controls were included. Derivatives of deoxycholic acid, cholic acid, and fatty acids were lower in serum, while urinary bile acids were higher in stage IV CRC patients (versus controls). Metabolites related to tryptophan and glutamate were found significantly altered in stage IV: upregulation of kynurenine and downregulation of indole pathways. This was linked to increased inflammatory protein and microbial metabolites and to the imbalance between virulent pro-inflammatory bacteria (Escherichia and Desulfovibrio) and symbiotic (Ruminococcus and Bifidobacterium) bacteria. Conclusions: E. coli-related tryptophan catabolism shift is shown through stage IV CRC as compared to controls. As a consequence, tryptophan/kynurenine metabolite may become a promising marker for detecting the failure to immune response during therapy. Full article

(This article belongs to the Special Issue Advancements in the Treatment of Colorectal Cancer)

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Review

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22 pages, 1319 KB

Open AccessReview

Circulating Tumor DNA-Guided Adjuvant and Post-Adjuvant Therapy in Resected Colorectal Cancer: From Molecular Residual Disease Detection to Proven Clinical Utility

by Thai Hau Koo, Rishi Chowdhary, Kirti Arora, Kelly Chun Lynn Lai and Andee Dzulkarnaen Zakaria

Biomedicines 2026, 14(8), 1674; https://doi.org/10.3390/biomedicines14081674 - 25 Jul 2026

Viewed by 577

Abstract

Colorectal cancer (CRC) kills approximately 850,000 people annually and is the second leading cause of cancer mortality worldwide. After curative-intent surgical resection, recurrence rates of 15–20% in stage II and 30–40% in stage III diseases highlight the fundamental limitations of pathological staging as the sole basis for adjuvant treatment decision-making. Circulating tumor DNA (ctDNA), which comprises tumor-derived cell-free DNA fragments shed into the bloodstream by dying cancer cells, offers a direct and dynamic readout of molecular residual disease (MRD) in the postoperative period. Because ctDNA clears within hours of macroscopically complete surgery, any persistently detectable postoperative signal reflects viable microscopic disease rather than surgical contamination. Over the past decade, evidence has matured rapidly from proof-of-concept observational studies to completed randomized clinical trials, culminating in the recent publication of DYNAMIC-III and ALTAIR in 2025–2026. The DYNAMIC trial established that ctDNA-guided management reduced adjuvant chemotherapy use from 27.9% to 15.3% in stage II colon cancer while maintaining an equivalent five-year recurrence-free survival (88% vs. 87%; difference 1.1%, 95% CI 5.8% to 8.0%). The GALAXY study confirmed ctDNA as the most powerful prognostic biomarker in resected CRC, with a disease-free survival hazard ratio of 11.99. Critically, DYNAMIC-III demonstrated that escalating chemotherapy intensity in ctDNA-positive stage III patients did not improve recurrence-free survival (HR 1.11, p = 0.6), and the phase III ALTAIR trial showed that trifluridine/tipiracil failed to significantly improve disease-free survival at the point of molecular recurrence (HR 0.79, p = 0.107). This review critically synthesizes the current evidence for ctDNA-guided treatment decisions in resected CRC across three therapeutic strategies: de-escalation in ctDNA-negative patients, escalation in ctDNA-positive patients, and post-adjuvant therapy at the point of molecular recurrence. Future progress requires biomarker-matched escalation strategies, adaptive trial designs, and formal validation of ctDNA clearance as a surrogate endpoint for predicting patient outcomes. Full article

(This article belongs to the Special Issue Advancements in the Treatment of Colorectal Cancer)

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28 pages, 1407 KB

Open AccessReview

Sucralose and the Gut–Immune Axis: Emerging Evidence Linking Dysbiosis, Barrier Alterations, and Implications for Colitis and Colorectal Cancer Immunotherapy

by Aranza Mejía-Muñoz, Jessica Cedillo Monter, Héctor Iván Saldívar-Cerón, Galileo Escobedo and Sonia Leon-Cabrera

Biomedicines 2026, 14(4), 917; https://doi.org/10.3390/biomedicines14040917 - 17 Apr 2026

Viewed by 4611

Abstract

Sucralose is one of the most widely used non-nutritive sweeteners and has long been considered metabolically inert and safe within established acceptable daily intake levels. However, emerging evidence suggests that chronic exposure to sucralose may alter gut microbial composition, epithelial barrier function, mucosal inflammation, and immune responses. This review examines current experimental and clinical evidence on the effects of sucralose on the gut–immune axis, with particular attention to its potential implications for colitis and colorectal cancer (CRC). Preclinical studies indicate that sucralose may reduce beneficial short-chain fatty acid-producing taxa, alter microbial metabolic pathways, disrupt epithelial barrier-related molecules, and promote inflammatory and immune changes associated with colitis severity and inflammation-driven tumorigenesis. Experimental evidence also suggests that sucralose may impair CD8⁺ T-cell fitness and reduce responsiveness to immune checkpoint inhibitors through microbiome-dependent mechanisms involving altered arginine and citrulline metabolism. Human studies further indicate that sucralose can modify gut and oral microbiome composition and influence metabolic responses, although these effects appear heterogeneous and context-dependent. Overall, the current literature suggests that sucralose may act as a modifier of microbiome–immune interactions in susceptible settings, but most mechanistic evidence remains preclinical, and human data are still insufficient to establish causality. These findings highlight the need for prospective studies to determine whether sucralose-associated microbial and immune alterations translate into clinically meaningful effects in colitis, CRC, and immunotherapy response. Full article

(This article belongs to the Special Issue Advancements in the Treatment of Colorectal Cancer)

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19 pages, 1075 KB

Open AccessReview

Circadian Clock Genes in Colorectal Cancer: From Molecular Mechanisms to Chronotherapeutic Applications

by Haoran Wang, Jieru Zhou, Suya Pang, Yiqing Mei, Gangping Li, Yu Jin and Rong Lin

Biomedicines 2026, 14(1), 110; https://doi.org/10.3390/biomedicines14010110 - 6 Jan 2026

Viewed by 1656

Abstract

Colorectal cancer (CRC) is a life-threatening malignancy, but our understanding of its pathogenic mechanisms remains incomplete—posing a major constraint on the development of effective therapeutic strategies. The transcription-translation feedback loop of clock genes (e.g., BMAL1, CLOCK, PER1/2/3, and CRY1/2) provides a promising novel avenue for deciphering the initiation and progression of CRC. Mounting evidence indicates that core circadian clock genes play pivotal roles in CRC oncogenesis by orchestrating the regulation of the cell cycle, epithelial–mesenchymal transition (EMT), metabolic reprogramming, and the tumor microenvironment. This review systematically summarizes the expression patterns and mechanistic roles of core clock genes in CRC, while elucidating their molecular underpinnings in tumor progression via key signaling cascades (e.g., Wnt/β-catenin and c-Myc/p21 pathways). We emphasize the associations between circadian disruption and CRC—including diagnostic markers, prognostic assessment, and chemosensitivity—and provide an in-depth discussion of chronotherapeutic strategies and their translational potential. Finally, we identify unaddressed scientific questions and propose future research directions to facilitate the development of novel targeted therapies for CRC. Full article

(This article belongs to the Special Issue Advancements in the Treatment of Colorectal Cancer)

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