Targeting Ferroptosis to Overcome Radioresistance and Enhance Immunotherapy in Colorectal Cancer

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Locally advanced rectal cancer treatment often involves total neoadjuvant therapy (TNT), integrating radiotherapy and chemotherapy.
• Radiotherapy response in rectal cancer is heterogeneous, with some tumors showing resistance, leading to incomplete tumor control and toxicity.
• Understanding the biological basis of radiation sensitivity is crucial for improving rectal cancer treatment outcomes.

Purpose of the Study:

• To examine the molecular mechanisms linking radiation-induced oxidative stress to ferroptosis and tumor immunity in colorectal cancer.
• To focus on the clinical context of radiotherapy in rectal cancer and its interaction with ferroptosis.
• To explore therapeutic strategies combining radiotherapy, ferroptosis targeting, and immunotherapy for radioresistant colorectal cancers.

Main Methods:

• Review of literature on radiation-induced oxidative stress, reactive oxygen species (ROS), DNA damage, and lipid peroxidation.
• Analysis of ferroptosis pathways, including system Xc- (SLC7A11/SLC3A2), glutathione, GPX4, iron metabolism, and lipid remodeling.
• Investigation of the interplay between ferroptosis, antitumor immunity, and immune checkpoint inhibitors in colorectal cancer.

Main Results:

• Ionizing radiation induces ROS and DNA damage, potentially triggering ferroptosis via lipid peroxidation when antioxidant systems are overwhelmed.
• Ferroptosis is regulated by metabolic pathways and intersects with antitumor immunity, influencing immune activation through released signals.
• Interferon-γ can suppress SLC7A11, promoting ferroptosis, while microsatellite-stable (MSS) rectal cancers show limited response to immunotherapy.

Conclusions:

• Ferroptosis represents a link between tumor metabolic vulnerability and immune-mediated cytotoxicity, relevant to colorectal cancer.
• Strategies to enhance tumor immunogenicity are needed for MSS rectal cancers, which are typically less responsive to immunotherapy.
• Integrating radiotherapy with ferroptosis-targeting agents and immunotherapy holds therapeutic potential to overcome radioresistance and improve outcomes.