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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\u2014both histopathological (pTRG) and MRI-based (mrTRG)\u2014are 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 of Wnt\/\u03b2-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\u2014particularly an enrichment of <jats:italic>Bacteroides<\/jats:italic> species\u2014is 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.<\/jats:p>","DOI":"10.1007\/s12029-025-01324-7","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T15:14:04Z","timestamp":1760541244000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Overcoming the Challenge: A Comprehensive Review of Neoadjuvant Treatment Resistance in Rectal Cancer"],"prefix":"10.1007","volume":"56","author":[{"given":"Alexandru","family":"Micu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Diaconescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corina-Elena","family":"Minciuna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodora","family":"Manuc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona Olimpia","family":"Dima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Droc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlad","family":"Herlea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Becheanu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adina Emilia","family":"Croitoru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalin","family":"Vasilescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"1324_CR1","doi-asserted-by":"publisher","first-page":"719","DOI":"10.6004\/jnccn.2015.0087","volume":"13","author":"AB Benson","year":"2015","unstructured":"Benson AB, Venook AP, Bekaii-Saab T, Chan E, Chen Y-J, Cooper HS, et al. 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