Recent advances in novel targeting mechanisms for colorectal cancer.

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.