Li Zhiping, Wang Hailing, Liu Yan, Gemingnuer Ahequeli, Wang Yinan, Meng Xin
School of Pharmacy, Heilongjiang University of Chinese Medicine, No. 24 Heping Road, Harbin, 150040, People's Republic of China.
Clin Transl Oncol. 2025 Jul 11. doi: 10.1007/s12094-025-03990-2.
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with treatment complicated by drug resistance, metastasis, and tumor heterogeneity. In recent years, with deeper insights into tumor biology, various novel targeting mechanisms have been discovered and garnered increasing attention. Among these mechanisms, metabolic reprogramming, cell death mechanisms, and signaling pathways are particularly critical, as they not only govern fundamental biological processes of CRC but also offer a wealth of clinically actionable targets. Metabolic alterations, particularly in methionine, folate, serine, and polyamine pathways, have been implicated in CRC pathogenesis, offering potential therapeutic targets. Noncoding RNAs, such as long noncoding RNAs CKMT2-AS1 and H19, and microRNA-375-3p, regulate critical signaling pathways like AKT/mTOR, TP53, and TYMS, influencing tumor proliferation, apoptosis, and chemotherapy resistance. Additionally, gut microbiota modulation, including interventions like defatted rice bran supplementation and prebiotic-based nanoparticle therapies, presents novel strategies to enhance immune responses and sensitize tumors to chemotherapy. Extracellular vesicles have emerged as key players in immune evasion and metastasis, with small extracellular vesicle-derived miRNAs promoting tumor progression and liver metastasis. Furthermore, mechanical stress signaling through pathways such as FAK-Rho-ROCK and Wnt-YAP1 regulates CRC cell migration, invasion, and stem cell enrichment, offering additional therapeutic avenues. Targeting these multifaceted mechanisms offers promising strategies to enhance CRC treatment efficacy, particularly in overcoming drug resistance and preventing metastasis. Currently, there is a lack of such reviews that systematically integrate novel targeting mechanisms in CRC, particularly those focusing on emerging mechanisms, metabolic reprogramming, cell death mechanisms, and signaling pathways, leaving a clear gap in the current literature. This review provides a comprehensive synthesis of recent advances in these areas, offering novel therapeutic insights to address critical challenges such as metastasis, chemoresistance, and immune evasion.
结直肠癌（CRC）仍是全球癌症相关死亡的主要原因，其治疗因耐药性、转移和肿瘤异质性而变得复杂。近年来，随着对肿瘤生物学的深入了解，各种新型靶向机制被发现并日益受到关注。在这些机制中，代谢重编程、细胞死亡机制和信号通路尤为关键，因为它们不仅控制着CRC的基本生物学过程，还提供了大量可用于临床的靶点。代谢改变，特别是在甲硫氨酸、叶酸、丝氨酸和多胺途径中的改变，与CRC发病机制有关，提供了潜在的治疗靶点。非编码RNA，如长链非编码RNA CKMT2-AS1和H19，以及微小RNA-375-3p，调节AKT/mTOR、TP53和TYMS等关键信号通路，影响肿瘤增殖、凋亡和化疗耐药性。此外，肠道微生物群调节，包括补充脱脂米糠和基于益生元的纳米颗粒疗法等干预措施，提出了增强免疫反应和使肿瘤对化疗敏感的新策略。细胞外囊泡已成为免疫逃逸和转移的关键因素，小细胞外囊泡衍生的微小RNA促进肿瘤进展和肝转移。此外，通过FAK-Rho-ROCK和Wnt-YAP1等途径的机械应力信号调节CRC细胞的迁移、侵袭和干细胞富集，提供了额外的治疗途径。针对这些多方面的机制提供了有前景的策略来提高CRC治疗效果，特别是在克服耐药性和预防转移方面。目前，缺乏系统整合CRC新型靶向机制的综述，特别是那些关注新兴机制、代谢重编程、细胞死亡机制和信号通路的综述，这在当前文献中留下了明显的空白。本综述全面综合了这些领域的最新进展，为应对转移、化疗耐药和免疫逃逸等关键挑战提供了新的治疗见解。
