Non-steroidal anti-inflammatory drugs induce immunogenic cell death in suppressing colorectal tumorigenesis

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Non-steroidal anti-inflammatory drugs (NSAIDs) are linked to decreased colorectal cancer (CRC) risk.
• The precise mechanisms of NSAID-mediated colorectal tumorigenesis suppression are not fully understood.
• Previous research indicated NSAIDs trigger tumor cell death via death receptor (DR) signaling and BID-mediated synthetic lethality.

Purpose of the Study:

• To elucidate the mechanism by which NSAIDs suppress colorectal tumor formation.
• To investigate the role of endoplasmic reticulum (ER) stress and BID in NSAID-induced tumor suppression.
• To explore the immunogenic effects of NSAIDs in colorectal cancer.

Main Methods:

• Investigated NSAID-induced ER stress activation of DR signaling and BID.
• Assessed NSAID-induced immunogenic cell death (ICD) hallmarks in colorectal cancer (CRC) and colonic cells.
• Analyzed tumor-infiltrating lymphocytes (TILs) in APC^Min/+ mice polyps.
• Examined effects of ER stress inhibition or BID deletion on NSAID efficacy.
• Evaluated ER stress and TILs in human advanced adenomas from NSAID-treated patients.

Main Results:

• NSAIDs induce ER stress, activating DR signaling and BID, crucial for tumor suppression.
• NSAID treatment promoted ICD in CRC cells and colonic cells with APC loss.
• Elevated TILs were observed in NSAID-treated APC^Min/+ mice polyps.
• Inhibition of ER stress or deletion of BID abolished the anti-tumor and immunogenic effects of NSAIDs.
• Human advanced adenomas from NSAID users showed increased ER stress and TILs.

Conclusions:

• NSAIDs suppress colorectal tumor formation through ER stress and BID-dependent ICD.
• This mechanism restores immunosurveillance by increasing TILs.
• NSAIDs may represent a therapeutic strategy for colorectal cancer by modulating the immune response.