Autophagy regulation of pyroptosis and ferroptosis: a new strategy for colorectal cancer treatment.

Colorectal cancer (CRC), a highly prevalent malignant neoplasm worldwide, poses significant challenges in clinical management due to resistance to radiotherapy and chemotherapy. Notably, chemoresistance in CRC is frequently linked to elevated autophagy levels, prompting extensive exploration of combination therapies that integrate chemotherapeutic agents with autophagy modulators, including both inducers and inhibitors. Moreover, the induction of programmed cell death (PCD) in tumor cells has the potential to improve the therapeutic efficacy of anti-tumor treatments and address key challenges related to drug resistance. Pyroptosis and ferroptosis, two distinct types of PCD, have emerged as potential tumor-suppressive mechanisms owing to their unique molecular characteristics. Increasing evidence supports functional crosstalk between these two processes. Autophagy exerts complex regulatory effects on pyroptosis and ferroptosis through multiple functional subtypes. Growing evidence indicates that various pharmacological agents, small molecules, nanocarrier-based delivery systems, and specific autophagic pathways can selectively induce pyroptosis or ferroptosis. Moreover, combining autophagy modulators with standard radiotherapeutic or chemotherapeutic regimens holds significant promise for enhancing treatment outcomes and restore drug sensitivity in CRC. This review systematically summarizes the molecular mechanisms underlying pyroptosis and ferroptosis along with their roles in CRC pathogenesis, elucidates the central regulatory function of autophagy, discusses innovative strategies leveraging autophagy-mediated activation of pyroptosis and ferroptosis, and evaluates the synergistic potential inherent of integrating autophagy modulation with established treatment modalities. Finally, current challenges pertaining to mechanistic research and clinical translation are critically assessed to provide a robust theoretical foundation for future advances in CRC therapeutics.