Ferroptosis in colorectal cancer: Molecular mechanisms, therapeutic opportunities, and challenges

Colorectal cancer (CRC) represents a substantial global health challenge.Classical treatment modalities are prone to triggering acquired drug resistance, which impairs therapeutic efficacy and accelerates tumor progression and recurrence.This narrative review summarizes the regulatory mechanisms of ferroptosis in the occurrence and progression of CRC, together with its immunomodulatory effects.Literature was retrieved from PubMed, Web of Science, and EMBASE from 1991 until 2026, using keywords including CRC, ferroptosis, lipid peroxidation, glutathione peroxidase 4, acyl-CoA synthetase long-chain family 4, AMP-activated protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (NRF2), iron metabolism, immunotherapy, and drug resistance.In CRC, iron metabolic dysregulation, enhanced lipid peroxidation, and impaired antioxidant defense systems have been implicated in promoting ferroptosis.Nevertheless, ferroptosis sensitivity differs significantly among distinct molecular subtypes of CRC.AMPK and NRF2 may modulate the sensitivity of tumor cells to ferroptosis; however, these effects are largely derived from cell line and preclinical model studies.In addition, limited preclinical evidence from CRC models suggests that ferroptosis may remodel the tumor microenvironment (TME), potentially facilitating the infiltration of cytotoxic CD8+ T lymphocytes and alleviating the accumulation of immunosuppressive cell populations such as regulatory T cells and myeloid-derived suppressor cells.Ferroptosis elicits direct cytotoxic effects on CRC cells and may reshape the TME to favor CD8+ T-cell recruitment.However, it carries risks of triggering ferroptotic exhaustion in immune effector cells.Such immunomodulatory mechanisms still lack validation using CRC patient-derived organoids, xenografts, and clinical specimens, which compromises their translational value.Despite such evidence gaps, ferroptosis remains a tentative candidate target for combinatorial immunotherapy against CRC, one that requires rigorous clinical validation.We further identify key unresolved questions, including the lack of validated companion biomarkers, the dual 4 / 53 role of ferroptosis in tumor immunity, and the urgent need for TME-restricted delivery strategies.