Curcumin enhances GSDME-mediated pyroptosis to potentiate PD-1/PD-L1 immune checkpoint blockade in colorectal cancer

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Microsatellite-stable colorectal cancer (MSS CRC) shows limited response to PD-1/PD-L1 immunotherapy.
• Pyroptosis induction is a potential strategy to resensitize MSS tumors, but GSDME expression is often low in CRC.
• GSDME is a critical executioner of pyroptosis.

Purpose of the Study:

• To investigate curcumin's (CUR) role in potentiating GSDME-dependent pyroptosis in MSS CRC.
• To determine if CUR can enhance the efficacy of PD-1/PD-L1 blockade in MSS CRC.
• To elucidate the molecular mechanisms underlying CUR's effects on GSDME and pyroptosis.

Main Methods:

• Utilized MSS-type CT26 and HT29 cell lines to study CUR's effects on GSDME expression and pyroptosis.
• Investigated the role of the ubiquitin-proteasome system (UPS) and caspase-3/GSDME signaling axis.
• Assessed the impact of CUR-enhanced pyroptosis on tumor-infiltrating immune cells in CT26 tumor models.
• Evaluated the therapeutic efficacy of CUR combined with anti-PD-1 therapy in CT26 tumors, including GSDME-knockout models.

Main Results:

• Curcumin (CUR) was identified as a potentiator of GSDME-dependent pyroptosis in CRC.
• CUR upregulated GSDME expression by inhibiting the UPS and activated the caspase-3/GSDME axis, increasing pyroptosis in MSS cell lines.
• In CT26 tumors, CUR treatment reshaped tumor immunity and enhanced anti-PD-1 therapy efficacy.
• The synergistic effect of CUR and PD-1 blockade was dependent on the caspase-3/GSDME axis, as it was abolished in GSDME-knockout tumors.

Conclusions:

• Curcumin effectively induces GSDME-dependent pyroptosis in MSS CRC.
• CUR acts as a safe and effective adjuvant to enhance PD-1/PD-L1 blockade in MSS CRC, especially in tumors with low GSDME expression.
• The caspase-3/GSDME axis is crucial for the combined therapeutic benefit of CUR and PD-1 blockade.