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Perspectives on the Efficacy and Biomarkers of Immunotherapy and Targeted Therapy for Patients with Colorectal Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 15474

Special Issue Editor

Dr. Ibrahim Halil Sahin

E-Mail Website
Guest Editor
Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Interests: gastrointestinal oncology; targeted therapy; immunotherapy

Special Issue Information

Dear Colleagues,

In this Special Issue, we intend to provide a comprehensive update on precision medicine treatments and immunotherapeutics for patients with colorectal cancer. The scope of this Special Issue will include the efficacy of novel targeted therapeutic agents and immune checkpoint inhibitors, treatment-related adverse events and their management and the role of biomarkers for treatment selection as well as molecular underpinnings of mechanisms of resistance covering these novel agents.

This Special Issue aims to focus on these topics, amongst others. In this Special Issue, original research articles and reviews are welcome.

I look forward to receiving your contributions.

Dr. Ibrahim Halil Sahin
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • colorectal cancer
  • precision medicine
  • targeted therapeutics
  • immunotherapy
  • KRAS
  • BRAF
  • HER2
  • biomarkers

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Published Papers (6 papers)

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Research

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16 pages, 9946 KB  
Article
Histone Deacetylase-2 Expression in Colorectal Cancer: An Immunohistochemical Study and Its Clinicopathological Significance
by Nikolaos Garmpis, Afroditi Nonni, Dimitrios Dimitroulis, Eleni I. Effraimidou, Anna Garmpi, Miltiadis-Panagiotis Papandroudis, Konstantinos Kontzoglou and Christos Damaskos
Cancers 2026, 18(9), 1466; https://doi.org/10.3390/cancers18091466 - 2 May 2026
Viewed by 793
Abstract
Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality and is characterized by substantial molecular heterogeneity, including epigenetic dysregulation. Histone acetylation, regulated by histone acetyltransferases and histone deacetylases (HDAC), has been implicated in CRC development and progression. The aim of [...] Read more.
Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality and is characterized by substantial molecular heterogeneity, including epigenetic dysregulation. Histone acetylation, regulated by histone acetyltransferases and histone deacetylases (HDAC), has been implicated in CRC development and progression. The aim of the present study was to evaluate HDAC-2 expression in CRC and investigate its association with clinicopathological parameters and patient outcomes. Methods: In this retrospective study, tumor tissue samples from 77 patients with CRC and documented recurrence were examined. HDAC-2 expression was assessed by immunohistochemistry and classified as low or high using a semi-quantitative scoring system. Associations with clinicopathological parameters and survival outcomes (disease-free survival, DFS; overall survival, OS) were analyzed. Results: High HDAC-2 expression was associated with younger patient age and earlier disease recurrence, while its association with overall survival was borderline. Conclusions: HDAC-2 expression may have clinicopathological relevance in CRC, particularly in relation to recurrence-related outcomes, although larger studies are needed to confirm its prognostic significance. Full article
(This article belongs to the Special Issue Perspectives on the Efficacy and Biomarkers of Immunotherapy and Targeted Therapy for Patients with Colorectal Cancer)
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12 pages, 1173 KB  
Article
A Comprehensive Molecular and Clinical Study of Patients with Young-Onset Colorectal Cancer
by Elham Nasrollahi, Shuaichao Wang, Rami Yanes, Cyndi Gonzalez Gomez, Tara Magge, Abigail Overacre, Ronan Hsieh, Ashley Mcfarquhar, Curtis Tatsuoka, Aatur Singhi, Anwaar Saeed and Ibrahim Halil Sahin
Cancers 2025, 17(17), 2763; https://doi.org/10.3390/cancers17172763 - 25 Aug 2025
Cited by 1 | Viewed by 2111
Abstract
Background: Young-onset colorectal cancer (YO-CRC) has emerged as a distinct clinical entity, often presenting at advanced stages. Despite the increasing incidence, the molecular and clinical underpinnings of YO-CRC remain underexplored. This study aims to characterize the clinical and molecular features of YO-CRC [...] Read more.
Background: Young-onset colorectal cancer (YO-CRC) has emerged as a distinct clinical entity, often presenting at advanced stages. Despite the increasing incidence, the molecular and clinical underpinnings of YO-CRC remain underexplored. This study aims to characterize the clinical and molecular features of YO-CRC and to evaluate their impact on OS. Methods: We reviewed 110 patients diagnosed with YO-CRC at our institution who underwent next-generation sequencing. Demographic, clinical, and molecular data, including age, gender, race, tumor location, cancer stage, and mutation status (KRAS, NRAS, BRAF, POLE, ERBB-2/HER2, microsatellite status), were collected by reviewing electronic medical records. For OS analysis, we focused on patients diagnosed with de novo stage IV. Cox proportional hazards regression and Kaplan–Meier survival analysis were utilized to assess the association of these factors with OS, with statistical significance determined by a p-value threshold of <0.05. Results: Among 110 patients, n = 44 (40%) presented with local disease (stage 1–3), while n = 66 (60%) presented with de novo metastatic disease at the time of diagnosis. The median age at diagnosis was 44.5 years. The cohort consisted of 64% males and 36% females, with 84% of patients identified as White. Most tumors were left-sided (77%), including the distal colon/sigmoid (44%) and rectum (33%). KRAS and BRAF mutations were present in 36% and 5.5%, respectively. ERBB-2/HER2 amplification and microsatellite instability were observed in 4.5% and 6.4%, respectively. Tumor mutation burden (TMB) was <10 in 57% of patients, with 14% having TMB > 20. CNV analysis revealed that 14% of patients had copy gains, 12% had concurrent gains/losses, and 31% had copy losses. Among 66 patients with de novo metastatic disease, 44% had died by the time of analysis, with a median overall survival (OS) of 43.6 months (95% CI, 28.7—not reached). KRAS mutations were found to be significantly associated with worse survival outcomes. Cox regression analysis reveals the prognostic significance of KRAS status, with a hazard ratio (HR) of 3.52 (95% CI: 1.59–7.76, p = 0.002), indicating a significantly higher risk of death for KRAS-mutant YO-CRC patients. Conclusions: Patients with YO-CRC are more likely to present with de novo metastatic disease and left-sided tumors with distinct molecular characteristics. KRAS mutations are a key prognostic factor in YO-CRC, highlighting the need for therapeutic interventions to improve outcomes in this high-risk group. Full article
(This article belongs to the Special Issue Perspectives on the Efficacy and Biomarkers of Immunotherapy and Targeted Therapy for Patients with Colorectal Cancer)
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Review

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20 pages, 1133 KB  
Review
The Evolving Role for Repeat Molecular Testing in Metastatic Colorectal Cancer
by Nicholas D. Kendsersky, Mariah R. Erlick, Emerson Y. Chen and Hagen F. Kennecke
Cancers 2026, 18(6), 1007; https://doi.org/10.3390/cancers18061007 - 20 Mar 2026
Viewed by 1115
Abstract
Next-generation sequencing (NGS) has impacted the treatment landscape for mCRC, leading to improved outcomes through the use of molecularly targeted and immune checkpoint inhibitor therapies. The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) recommend, at a minimum, [...] Read more.
Next-generation sequencing (NGS) has impacted the treatment landscape for mCRC, leading to improved outcomes through the use of molecularly targeted and immune checkpoint inhibitor therapies. The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) recommend, at a minimum, initial testing to assess RAS, BRAF, HER2, and microsatellite instability (MSI)/mismatch repair (MMR) status, as these results determine therapeutic eligibility. Broader testing to identify the eligibility for tumor-agnostic therapy for a tumor mutation burden (TMB), NTRK gene fusions, and RET fusions is encouraged for all patients with advanced solid tumors. Patients with metastatic disease may develop progressive disease, often as a result of adaptive resistance mechanisms and selective therapeutic pressure on disease heterogeneity. Repeat biomarker testing at progression has the potential to define these resistance mechanisms and to guide the next therapy or clinical trial enrollment. While these practices have become more commonplace, unified guidelines have yet to be established. In this review of the literature, we evaluate the advantages and pitfalls of sequential biomarker testing during disease progression in patients with mCRC. Full article
(This article belongs to the Special Issue Perspectives on the Efficacy and Biomarkers of Immunotherapy and Targeted Therapy for Patients with Colorectal Cancer)
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19 pages, 347 KB  
Review
Decoding Immunotherapy Response in Colorectal Cancer: Translational Insights Beyond MSI
by Chiara Cataldi, Beliz Bahar Karaoğlan, Elena Liotta and Sara De Dosso
Cancers 2026, 18(5), 852; https://doi.org/10.3390/cancers18050852 - 6 Mar 2026
Viewed by 1089
Abstract
Background/Objectives: Immune checkpoint inhibitors (ICIs) are among the transformative and manageable systemic therapies for several cancer types, including colorectal cancer (CRC). Nevertheless, their clinical benefit is limited to mismatch-deficient or microsatellite instability-high diseases, which represent only a small percentage of cases. Despite [...] Read more.
Background/Objectives: Immune checkpoint inhibitors (ICIs) are among the transformative and manageable systemic therapies for several cancer types, including colorectal cancer (CRC). Nevertheless, their clinical benefit is limited to mismatch-deficient or microsatellite instability-high diseases, which represent only a small percentage of cases. Despite this initial major and stringent selection, primary and acquired resistance remain clinically relevant. Therefore, the identification of additional biomarkers is essential to refine patient selection and guide rational combinational strategies. This review aims to summarize the current evidence regarding established and emerging biomarkers of response and resistance to ICIs in CRC. Methods: This narrative review identified and synthesized relevant clinical trials, translational studies, and reviews through a literature search of emerging biomarkers of immunotherapy response in colorectal cancer. Results: Deficient mismatch repair/high microsatellite instability remains the most reliable predictive biomarker of ICI response, emphasized by high tumor mutational burden, POLE/POLD mutations, and specific tumor microenvironment features. Emerging indicators, including molecular alterations, antigen presentation machinery integrity, PD-L1-mediated signaling, microbiome connections, and circulating tumor DNA kinetics, have demonstrated significant potential as sources for therapeutic response prediction and have informed the development of innovative combination strategies in both MSI-H and MSS CRCs. Conclusions: Immunotherapy response in CRC is determined by a complex interplay between tumor-intrinsic, immune, microenvironmental, and systemic factors. Integrating multiple biomarkers may provide superior stratification and guide therapeutic strategies. Prospective validation and standardized biomarker assessment will be imperative to translate these insights into clinical practice. Full article
(This article belongs to the Special Issue Perspectives on the Efficacy and Biomarkers of Immunotherapy and Targeted Therapy for Patients with Colorectal Cancer)
23 pages, 1011 KB  
Review
Circulating Tumor DNA-Based Assessment of Minimal Residual Disease in Colorectal Cancer: Prognostic and Predictive Implications
by Ahmet Anil Ozluk, Will Colley, Zeynep Beyza Arik, Osman Kostek, Aakash Sunkari, Midhun Malla and Mehmet Akce
Cancers 2026, 18(5), 754; https://doi.org/10.3390/cancers18050754 - 26 Feb 2026
Viewed by 1385
Abstract
Circulating tumor DNA (ctDNA) has emerged as a promising and versatile biomarker in colorectal cancer (CRC), providing real-time insights into the tumor burden, minimal residual disease (MRD), and treatment response across both early and metastatic stages. In patients with resected stage II–III CRC, [...] Read more.
Circulating tumor DNA (ctDNA) has emerged as a promising and versatile biomarker in colorectal cancer (CRC), providing real-time insights into the tumor burden, minimal residual disease (MRD), and treatment response across both early and metastatic stages. In patients with resected stage II–III CRC, post-operative ctDNA positivity is a robust predictor of recurrence and may outperform traditional clinicopathologic risk factors. It can facilitate adjuvant therapy discussions; however, treatment escalation or de-escalation based solely on ctDNA results is not yet supported by available interventional data. In the metastatic setting, ctDNA-based techniques could provide non-invasive molecular profiling and a monitoring response to systemic therapies. Peripheral blood-based techniques could also help detect emerging resistance to systemic therapy. Emerging evidence highlights that quantitative assessment of ctDNA dynamics, including the baseline burden and post-treatment clearance, could further refine risk stratification and inform treatment personalization. Collectively, ctDNA represents a promising and evolving biomarker with well-established prognostic and emerging predictive potential and is poised to support precision oncology across the continuum of CRC. Full article
(This article belongs to the Special Issue Perspectives on the Efficacy and Biomarkers of Immunotherapy and Targeted Therapy for Patients with Colorectal Cancer)
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20 pages, 963 KB  
Review
Targeting the KRAS Oncogene for Patients with Metastatic Colorectal Cancer
by Ruoyu Miao, James Yu and Richard D. Kim
Cancers 2025, 17(9), 1512; https://doi.org/10.3390/cancers17091512 - 30 Apr 2025
Cited by 12 | Viewed by 7981
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, with KRAS mutations occurring in approximately 40% of cases. These mutations drive tumorigenesis through the constitutive activation of key signaling pathways, such as RAS-RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR, contributing to therapeutic resistance and [...] Read more.
Colorectal cancer (CRC) is one of the most common cancers worldwide, with KRAS mutations occurring in approximately 40% of cases. These mutations drive tumorigenesis through the constitutive activation of key signaling pathways, such as RAS-RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR, contributing to therapeutic resistance and poor prognosis. Advances in molecular biology have led to significant breakthroughs, including the development of KRAS G12C inhibitors, such as sotorasib and adagrasib, which have shown promise in clinical trials. However, their efficacy is limited to a small subset of KRAS-mutant CRC, and resistance mechanisms often emerge through compensatory pathway activation. Combination strategies, including KRAS inhibitors with anti-EGFR agents, have been explored in trials like KRYSTAL-1 and CodeBreaK 300. Emerging research highlights the role of the tumor microenvironment in immune evasion and therapeutic resistance, offering opportunities for novel immunotherapy approaches, including KRAS neoantigen vaccines and adoptive T-cell therapy. Despite these advancements, challenges such as intratumoral heterogeneity, limited immune infiltration, and non-G12C KRAS mutations remain significant hurdles. This review provides a comprehensive overview of the molecular mechanisms, current advances and challenges, and future prospects in the management of KRAS-mutant CRC. Full article
(This article belongs to the Special Issue Perspectives on the Efficacy and Biomarkers of Immunotherapy and Targeted Therapy for Patients with Colorectal Cancer)
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