结直肠癌 (CRC) 是一项重大的公共卫生挑战，5-氟尿嘧啶 (5-FU) 耐药性是有效治疗的主要障碍。尽管取得了进展，但由于药物转运的改变、细胞凋亡的逃避、细胞周期动力学失调、肿瘤微环境 (TME) 相互作用和细胞外囊泡 (EV) 介导的耐药途径等复杂机制，对 5-FU 的耐药性仍然很强大。传统化疗通常会导致高毒性，因此需要具有更好疗效和安全性的替代方法。植物化学物质 (PC) 和 EV 提供了有前景的 CRC 治疗策略。 PC 来自天然来源，通常表现出较低的毒性，并且可以针对涉及癌症进展和耐药性的多种途径。 EV 可以促进靶向药物输送、调节免疫反应并与 TME 相互作用以使癌细胞对治疗敏感。然而，PC 和工程化 EV 在克服 5-FU 耐药性和重塑 CRC 中免疫抑制性 TME 方面的潜力仍未得到充分探索。解决这一差距对于确定具有增强疗效和降低毒性的创新疗法至关重要。本综述探讨了结直肠癌中 5-FU 耐药的多方面机制，并评估了 PC 与 5-FU 联合使用的协同效应，以提高治疗效果，同时最大限度地减少不良反应。此外，它还研究了工程化 EV 通过充当药物输送工具和调节 TME 来克服 5-FU 耐药性。通过综合现有知识并弥补研究空白​​，本综述增强了对 CRC 5-FU 耐药性的学术理解，强调了涉及 PC 和 EV 的跨学科方法彻底改变 CRC 治疗的潜力。进一步的研究和临床验证对于将这些发现转化为改善的患者治疗结果至关重要。

Colorectal cancer (CRC) is a significant public health challenge, with 5-fluorouracil (5-FU) resistance being a major obstacle to effective treatment. Despite advancements, resistance to 5-FU remains formidable due to complex mechanisms such as alterations in drug transport, evasion of apoptosis, dysregulation of cell cycle dynamics, tumor microenvironment (TME) interactions, and extracellular vesicle (EV)-mediated resistance pathways. Traditional chemotherapy often results in high toxicity, highlighting the need for alternative approaches with better efficacy and safety. Phytochemicals (PCs) and EVs offer promising CRC therapeutic strategies. PCs, derived from natural sources, often exhibit lower toxicity and can target multiple pathways involved in cancer progression and drug resistance. EVs can facilitate targeted drug delivery, modulate the immune response, and interact with the TME to sensitize cancer cells to treatment. However, the potential of PCs and engineered EVs in overcoming 5-FU resistance and reshaping the immunosuppressive TME in CRC remains underexplored. Addressing this gap is crucial for identifying innovative therapies with enhanced efficacy and reduced toxicities. This review explores the multifaceted mechanisms of 5-FU resistance in CRC and evaluates the synergistic effects of combining PCs with 5-FU to improve treatment efficacy while minimizing adverse effects. Additionally, it investigates engineered EVs in overcoming 5-FU resistance by serving as drug delivery vehicles and modulating the TME. By synthesizing the current knowledge and addressing research gaps, this review enhances the academic understanding of 5-FU resistance in CRC, highlighting the potential of interdisciplinary approaches involving PCs and EVs for revolutionizing CRC therapy. Further research and clinical validation are essential for translating these findings into improved patient outcomes.