Methuosis caused by dysregulated macropinocytosis, a promising tumor therapeutic strategy

Nonapoptotic programmed cell death (PCD) has been recognized as potential alternative target for increasing chemosensitivity and augmenting antitumor efficacy. Among various types of nonapoptotic PCD, methuosis has gotten increasing attention recently, largely due to its unique morphological features and potential implications for apoptosis-resistant tumor therapy with negligible side effects. Methuosis is characterized by cytoplasmic vacuolization initiated by sustained macropinocytosis, concomitantly, the other cytotoxic agents from extracellular fluid can be delivered into cytoplasm of tumor cell via macropinocytosis, which can profoundly strengthen the combined antitumor efficacy. Since the initial description of methuosis in 2008, dozens of methuosis inducers have been identified. This review provides a comprehensive overview of the research progress on these methuosis inducers. Firstly, we depict the distinctive characteristics of methuosis compared to other types of nonapoptotic cell death, especially those with clear cytoplasmic vacuolization. Next, we summarize the monotherapy and underlying mechanisms of these methuosis inducers, and their synergistic antitumor effectiveness. Finally, we explore the advantages and challenges of triggering methuosis as an effective strategy for tumor therapy, highlight the key issues need to be further addressed, look forward to facilitating the transformation of mechanistic insights into clinically optimized therapeutic implementations.