Canagliflozin primes antitumor immunity by triggering PD-L1 degradation in endocytic recycling

Area of Science:

• Oncoimmunology
• Molecular Biology
• Cancer Therapeutics

Background:

• Tumor PD-L1 expression is a key target for cancer immunotherapy.
• Understanding PD-L1 regulation is crucial for improving immune checkpoint blockade efficacy.
• Novel strategies are needed to overcome tumor immune evasion.

Purpose of the Study:

• To investigate the regulatory mechanisms of PD-L1 expression.
• To evaluate the potential of SGLT2 inhibitors in modulating PD-L1 levels and anti-tumor immunity.
• To identify new therapeutic targets for oncoimmunotherapy.

Main Methods:

• Investigated the interaction between SGLT2 and PD-L1 at the plasma membrane and endosomes.
• Utilized mechanistic studies to elucidate PD-L1 degradation pathways.
• Employed mouse models and humanized immune-transformation models for in vivo validation.
• Analyzed clinical data from non-small cell lung cancer patients.

Main Results:

• Canagliflozin, an SGLT2 inhibitor, significantly suppressed PD-L1 expression and enhanced T cell-mediated cytotoxicity.
• SGLT2 inhibition disrupted PD-L1 localization, promoting its ubiquitination and proteasomal degradation.
• Canagliflozin treatment or SGLT2 silencing reduced tumor progression in preclinical models, comparable to PD-1 mAb therapy.
• High SGLT2 expression correlated with improved survival in PD-1 mAb-treated NSCLC patients.

Conclusions:

• SGLT2 is identified as a regulator of cell surface PD-L1.
• Canagliflozin provides a readily available small-molecule drug for PD-L1 degradation.
• Targeting SGLT2 presents a promising therapeutic strategy to overcome tumor immune evasion.