Abstract

Colorectal cancer (CRC) remains a significant global health challenge, necessitating the exploration of novel therapeutic strategies. Recent advancements in understanding regulated cell death (RCD) pathways have unveiled cuproptosis as a distinct form of RCD, triggered by copper accumulation and its direct binding to lipoylated proteins of the mitochondrial tricarboxylic acid (CAC) cycle. This review comprehensively synthesizes the current knowledge regarding cuproptosis, specifically focusing on its intricate mechanisms, its profound impact on the tumor microenvironment (TME) and immune responses, its utility as a prognostic and diagnostic biomarker, and the emerging therapeutic strategies leveraging cuproptosis in CRC. We delve into key molecular regulators such as FDX1, DLAT, and CDKN2A, elucidating their roles in modulating cuproptosis sensitivity and resistance. Furthermore, the immunogenic nature of cuproptosis, its interplay with other RCD pathways like ferroptosis, pyroptosis and disulfidptosis, and its influence on immune cell infiltration and function are thoroughly discussed. The review also highlights the development of cuproptosis-related gene and lncRNA signatures, as well as molecular subtyping, for predicting CRC prognosis and guiding personalized treatment. Finally, we explore innovative therapeutic approaches, including copper-based nanomaterials, small molecule modulators, and strategies targeting copper homeostasis, which hold immense promise for enhancing anti-tumor efficacy in CRC. This review underscores cuproptosis as a pivotal player in CRC pathophysiology and a compelling target for future therapeutic interventions.

Keywords:Cuproptosis; Colorectal cancer; Copper metabolism; Immunotherapy; Biomarkers; Targeted therapy; Tumor microenvironment; Regulated cell death