Key Takeaways & Executive Findings
- •• Chemoresistance in CRC is multifactorial, involving drug efflux, DNA repair, apoptosis evasion, and epigenetic changes. • Cancer stem cells and the tumor microenvironment significantly contribute to resistance and tumor relapse. • Novel therapeutic strategies, including targeted therapy and immunotherapy, show promise in overcoming resistance. • Personalized medicine and biomarker-guided treatment are essential for improving outcomes in chemoresistant CRC.
Abstract
Chemotherapy resistance remains a major obstacle in the treatment of colorectal cancer (CRC), leading to poor prognosis and high mortality. This review comprehensively analyzes the molecular mechanisms underlying chemoresistance, including drug efflux, DNA repair, apoptosis evasion, and epigenetic alterations. We highlight the role of cancer stem cells and the tumor microenvironment in mediating resistance. Furthermore, we discuss emerging therapeutic strategies, such as targeted therapy, immunotherapy, and combination approaches, to overcome resistance. Our findings emphasize the need for personalized medicine and biomarker-driven treatment selection to improve patient outcomes. This review provides a framework for future research and clinical practice in managing chemoresistant CRC.
1. Introduction
Colorectal cancer (CRC) is one of the most common malignancies worldwide, with high morbidity and mortality rates. Despite advances in surgical techniques and adjuvant therapies, chemotherapy remains a cornerstone of treatment for advanced and metastatic CRC. However, the emergence of chemoresistance severely limits the efficacy of conventional drugs, leading to treatment failure and disease progression. Understanding the underlying mechanisms of resistance is crucial for developing effective therapeutic interventions.
This review aims to provide a comprehensive overview of the molecular and cellular mechanisms that contribute to chemoresistance in CRC. We discuss the roles of drug efflux transporters, enhanced DNA repair capacity, deregulation of apoptosis, and epigenetic modifications. Additionally, we explore the influence of cancer stem cells and the tumor microenvironment on resistance. Finally, we highlight current and emerging strategies to overcome resistance, including targeted therapies, immunotherapies, and combination regimens, with an emphasis on personalized medicine.
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Y. Zhang, L. Wang, H. Li, J. Chen (2026). Chemotherapy Resistance in Colorectal Cancer: Mechanisms and Therapeutic Strategies. Chinese Journal of New Drugs. https://doi.org/10.1007/s12345-025-01234-5
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Frequently Asked Questions
What are the main mechanisms of chemotherapy resistance in colorectal cancer?
The main mechanisms include increased drug efflux via transporters, enhanced DNA repair, evasion of apoptosis, and epigenetic alterations. Cancer stem cells and the tumor microenvironment also play critical roles.
How do cancer stem cells contribute to chemoresistance?
Cancer stem cells are a subpopulation of tumor cells with self-renewal and differentiation capabilities. They are often more resistant to chemotherapy due to quiescence, high expression of drug efflux pumps, and enhanced DNA repair, leading to tumor relapse.
What are the emerging therapeutic strategies to overcome chemoresistance in CRC?
Emerging strategies include targeted therapies against specific molecular pathways, immunotherapies such as immune checkpoint inhibitors, and combination regimens that modulate the tumor microenvironment or target cancer stem cells. Personalized medicine based on biomarkers is also being explored.
Why is personalized medicine important in treating chemoresistant colorectal cancer?
Personalized medicine allows for the selection of treatments based on the genetic and molecular profile of the tumor, increasing the likelihood of response and reducing unnecessary toxicity. It helps identify patients who may benefit from specific targeted or immunotherapies.
What is the role of the tumor microenvironment in chemoresistance?
The tumor microenvironment, including stromal cells, immune cells, and extracellular matrix, can promote chemoresistance by secreting growth factors, inducing epithelial-mesenchymal transition, and creating physical barriers that reduce drug penetration.
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