Programmed Cell Death Pathways in Cholangiocarcinoma: Opportunities for Targeted Therapy

SIMPLE SUMMARY: Cholangiocarcinoma is a highly aggressive cancer that originates from the bile ducts. Traditional treatments have limited effectiveness, necessitating the exploration of new approaches. Recent studies have highlighted the importance of programmed cell death mechanisms, including apoptosis, ferroptosis, pyroptosis, and necroptosis, in the development and progression of cholangiocarcinoma. Targeting these cell death pathways may increase the susceptibility of cholangiocarcinoma cells to chemotherapy and immunotherapy. However, further research is necessary to fully understand the intricacies of programmed cell death in cholangiocarcinoma and potentially identify effective therapeutic strategies. ABSTRACT: Cholangiocarcinoma is a highly aggressive cancer arising from the bile ducts. The limited effectiveness of conventional therapies has prompted the search for new approaches to target this disease. Recent evidence suggests that distinct programmed cell death mechanisms, namely, apoptosis, ferroptosis, pyroptosis and necroptosis, play a critical role in the development and progression of cholangiocarcinoma. This review aims to summarize the current knowledge on the role of programmed cell death in cholangiocarcinoma and its potential implications for the development of novel therapies. Several studies have shown that the dysregulation of apoptotic signaling pathways contributes to cholangiocarcinoma tumorigenesis and resistance to treatment. Similarly, ferroptosis, pyroptosis and necroptosis, which are pro-inflammatory forms of cell death, have been implicated in promoting immune cell recruitment and activation, thus enhancing the antitumor immune response. Moreover, recent studies have suggested that targeting cell death pathways could sensitize cholangiocarcinoma cells to chemotherapy and immunotherapy. In conclusion, programmed cell death represents a relevant molecular mechanism of pathogenesis in cholangiocarcinoma, and further research is needed to fully elucidate the underlying details and possibly identify therapeutic strategies.