ArticleThe Journal of clinical investigation2023
Canagliflozin primes antitumor immunity by triggering PD-L1 degradation in endocytic recycling.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 71 citations in OpenAlex.
- Effect of henagliflozin on aging biomarkers in patients with type 2 diabetes: A multicenter, randomized, double-blind, placebo-controlled study.Cell reports. Medicine · 2025Trial
- Ubiquitin-driven regulation of immune checkpoints in lung cancer: Mechanisms and therapeutic implications (Review).Experimental and therapeutic medicine · 2026Review
- Association of sodium-glucose co-transport protein 2 inhibitor use with clinical outcomes in patients receiving immune checkpoint inhibitors: a pan-tumor propensity-matched analysis.The oncologist · 2026Article
- SGLT2 inhibition induces autophagic flux blockade and sensitizes pancreatic cancer to EGFR-targeted therapy.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- Dual Modulation of Senescence and Immune Checkpoints by Metformin and Dapagliflozin Attenuates Liver Fibrosis in a Thioacetamide-Induced Rat Model.Advanced pharmaceutical bulletin · 2026Article
- SGLT2 inhibitor use reduces progression and surgical intervention of persistent pulmonary nodules.Lung cancer (Amsterdam, Netherlands) · 2026Article
- Sodium-glucose co-transporter 2 inhibitors and obesity-associated cancers in people with type 2 diabetes: A real-world observational study.Diabetes, obesity & metabolism · 2026Observational
- Targeting IRF1-TRIM21 axis enhances anti-tumor immunity by promoting ubiquitin-mediated degradation of FGL1 in non-small cell lung cancer.Communications biology · 2026Article
- ROCK1 inhibition primes anti-tumor immunity in EGFR-mutant NSCLC by triggering PD-L1 degradation mediated by SMURF2.Molecular cancer · 2026Article
- Solute Carrier transporters in tumor metabolism and immune modulation: implications for therapy.Journal of translational medicine · 2026Review
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- Metabolic Concepts of Sodium-Glucose Cotransporter 2 Inhibitors-Based Therapies Against Hepatocarcinogenesis and Therapy Resistance in Hepatocellular Carcinoma.Life (Basel, Switzerland) · 2026Review
- Proanthocyanidins enhance antitumor immunity by promoting ubiquitin-proteasomal PD-L1 degradation via stabilization of LKB1 and SYVN1.The Journal of clinical investigation · 2026Article
- Paroxetine repurposing enhances antitumor immunity via SPOP-mediated PD-L1 ubiquitination and proteasomal degradation.Journal of experimental & clinical cancer research : CR · 2026Article
- Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications.Journal of biomedical science · 2026Review
- Small molecules targeting the PD-1/PD-L1 axis for cancer immunotherapy.Theranostics · 2026Review
- Sodium-Glucose Cotransporter 2 Inhibitors as Emerging Anticancer Agents.Diabetes & metabolism journal · 2026Review
- PTPN22 Dephosphorylates CBL to Inhibit PD-L1 Ubiquitination and Drive Immunosuppression in Renal Cell Carcinoma.International journal of biological sciences · 2026Article
- Synthetic Flozins in Cancer Prevention and Combination Strategies: Structural Insights and Therapeutic Potential.Molecules (Basel, Switzerland) · 2025Review
- Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia.Molecular metabolism · 2025Article
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Authors and funding
17 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Understanding the regulatory mechanisms of PD-L1 expression in tumors provides key clues for improving immune checkpoint blockade efficacy or developing novel oncoimmunotherapy. Here, we showed that the FDA-approved sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin dramatically suppressed PD-L1 expression and enhanced T cell-mediated cytotoxicity. Mechanistic study revealed that SGLT2 colocalized with PD-L1 at the plasma membrane and recycling endosomes and thereby prevented PD-L1 from proteasome-mediated degradation. Canagliflozin disturbed the physical interaction between SGLT2 and PD-L1 and subsequently allowed the recognition of PD-L1 by Cullin3SPOP E3 ligase, which triggered the ubiquitination and proteasome-mediated degradation of PD-L1. In mouse models and humanized immune-transformation models, either canagliflozin treatment or SGLT2 silencing significantly reduced PD-L1 expression and limited tumor progression - to a level equal to the PD-1 mAb - which was correlated with an increase in the activity of antitumor cytotoxic T cells. Notably, prolonged progression-free survival and overall survival curves were observed in the group of PD-1 mAb-treated patients with non-small cell lung cancer with high expression of SGLT2. Therefore, our study identifies a regulator of cell surface PD-L1, provides a ready-to-use small-molecule drug for PD-L1 degradation, and highlights a potential therapeutic target to overcome immune evasion by tumor cells.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.