Overcoming the Challenge: A Comprehensive Review of Neoadjuvant Treatment Resistance in Rectal Cancer

Sep 23, 2026

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Colorectal cancer (CRC) is the third most commonly diagnosed cancer and a major cause of cancer-related mortality, particularly among younger men, with about one-third of cases arising in the rectum. For patients with locally advanced rectal cancer, neoadjuvant therapy is standard, yet gains in 5-year survival remain modest. Accurate response assessment after neoadjuvant therapy is essential for selecting subsequent strategies, including eligibility for non-operative management. Resistance to neoadjuvant treatment is driven by molecular mechanisms such as RAS alterations, MSI-high biology, epigenetic dysregulation, DNA damage repair changes, and tumor microenvironment factors. Emerging data also link gut microbiota—especially Bacteroides enrichment—to reduced response, underscoring the need for personalized therapeutic approaches.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

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Abstract

Introduction

Journal of Gastrointestinal Cancer (2025) 56:205 [https://doi.org/10.1007/s12029-025-01324-7](https://doi.org/10.1007/s12029-025-01324-7) Overcoming the Challenge: A Comprehensive Review of Neoadjuvant Treatment Resistance in Rectal Cancer Alexandru Micu1,2 · Andrei Diaconescu1,2 · Corina‑Elena Minciuna1,2 · Teodora Manuc2,3 · Simona Olimpia Dima1,2,7 · Gabriela Droc2,4 · Vlad Herlea2,5 · Gabriel Becheanu2,3 · Adina Emilia Croitoru2,6 · Catalin Vasilescu1,2 Accepted: 28 September 2025 © The Author(s) 2025 Abstract Colorectal cancer (CRC) is the third most commonly diagnosed cancer and remains a leading cause of cancer-related mortality, particularly among younger men. Approximately one-third of colorectal cancers occur in the rectum. For patients with locally advanced rectal cancer, neoadjuvant therapy is considered the standard treatment approach. Despite advances in therapeutic approaches, improvements in the 5-year survival rate have been modest. Accurate assessment of tumor response to neoadjuvant therapy (NAT) is critical for guiding subsequent treatment strategies, especially when considering eligibility for non-operative management (NOM) . Common evaluation methods include digital rectal examination (DRE), magnetic resonance imaging (MRI), and high-definition flexible endoscopy (HDFE). Tumor regression grading (TRG) systems—both histopathological (pTRG) and MRI-based (mrTRG)—are valuable tools for quantifying treatment response and predicting long-term outcomes. However, resistance to NAT remains a significant clinical challenge and is driven by a complex interplay of molecular mechanisms. Genetic factors, such as RAS mutations, have been linked to resistance to chemoradiotherapy (CRT), while tumors exhibiting microsatellite instability (MSI-high) tend to respond poorly to CRT but may show favorable outcomes with immune checkpoint inhibitors. Epigenetic pathways, including dysregulation ofWnt/β-catenin and PI3K/AKT signaling, along with alterations in DNA damage repair mechanisms, further influence CRT sensitivity. The tumor microenvironment also plays a pivotal role in modulating therapy response. Elements such as immune cell infiltration, hypoxia, angiogenesis, and the presence of cancer-associated fibroblasts (CAFs) contribute to a pro-resistance landscape. Moreover, emerging evidence suggests that gut microbiota composition—particularly an enrichment of Bacteroides species—is associated with diminished response to NAT. Understanding these multifaceted biological interactions is essential for developing personalized and more effective therapeutic strategies, with the goal of enhancing response to NAT and ultimately improving clinical outcomes in patients with rectal cancer. Keywords Rectal cancer · Oncology · Treatment resistance · Neoadjuvant therapy · Response assessment * * 1 2 3 Andrei Diaconescu [andrei.diaconescu@umfcd.ro](andrei.diaconescu@umfcd.ro) [Corina-Elena Minciuna](Corina-Elena Minciuna)[ ](Corina-Elena Minciuna)[corina.minciuna@umfcd.ro](corina.minciuna@umfcd.ro) Department of General Surgery, Fundeni Clinical Institute, Bucharest, Romania “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Department of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest, Romania 4 Centre of Anaesthesia and Intensive Care, Fundeni Clinical Institute, Bucharest, Romania 5 Department of Pathology, Fundeni Clinical Institute, Bucharest, Romania 6 Department of Oncology, Fundeni Clinical Institute, Bucharest, Romania 7 Center of Excellence in Translational Medicine (CEMT), Fundeni Clinical Institute, Bucharest, Romania Introduction Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer and the third leading cause of cancer-related deaths in both men and women in the USA. Notably, it is the leading cause of cancer-related deaths among men under the age of 50 [1] . Approximately onethird of CRC cases occur in the rectum

FAQs

Why is response assessment after neoadjuvant therapy important in locally advanced rectal cancer?

Accurate assessment guides subsequent treatment choices, including whether patients may be eligible for non-operative management. It helps quantify treatment effect and supports better long-term decision-making.

What common methods are used to evaluate tumor response to neoadjuvant therapy?

Tumor response is commonly assessed using digital rectal examination (DRE), magnetic resonance imaging (MRI), and high-definition flexible endoscopy (HDFE). Tumor regression grading systems include histopathological (pTRG) and MRI-based (mrTRG) approaches.

Which biological factors contribute to resistance to neoadjuvant therapy?

Resistance is associated with molecular mechanisms such as RAS mutations, MSI-high status, and epigenetic dysregulation involving Wnt/β-catenin and PI3K/AKT signaling, as well as DNA damage repair alterations. The tumor microenvironment, including immune infiltration, hypoxia, angiogenesis, and cancer-associated fibroblasts (CAFs), also plays a key role.

Sep 23, 2026

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