Trigger Points of Necroptosis (RIPK1, RIPK3, and MLKL)-Promising Horizon or Blind Alley in Therapy of Colorectal Cancer?

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, due to the limited efficacy of current therapeutic strategies in advanced stages. Necroptosis, a regulated form of necrotic cell death mediated by receptor-interacting protein kinases RIPK1 and RIPK3, and the pseudokinase MLKL, has emerged as a potential alternative pathway to induce cancer cell death. Recent studies suggest that modulation of necroptosis may enhance antitumor immunity, overcome therapeutic resistance, and improve clinical outcomes in CRC. In this review, we systematically analyzed the current literature on the role of necroptosis in CRC, focusing on molecular mechanisms, experimental models, and therapeutic implications. By critically evaluating the available evidence, we aimed to determine whether targeting RIPK1, RIPK3, and MLKL, or other novel agents, represents a promising horizon or a blind alley in the development of novel CRC therapies.