2. Academic Validation
  3. Co-targeting the CD73-adenosinergic axis enhances the anti-tumor efficacy of anti-PD-L1 immunotherapy in bladder cancer

Co-targeting the CD73-adenosinergic axis enhances the anti-tumor efficacy of anti-PD-L1 immunotherapy in bladder cancer

  • Biomed Pharmacother. 2025 Jul:188:118188. doi: 10.1016/j.biopha.2025.118188.
Frederico Furriel 1,  Hugo Ferreira 2,  Gabriela Sampaio-Ribeiro 2,  Margarida Pereira 2,  Catarina Eloy 3,  Beatriz Neves 4,  Artur Paiva 5,  Belmiro Parada 6,  Célia Gomes 7
Affiliations

Affiliations

  • 1 University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal; Department of Urology, Unidade Local de Saúde da Região de Leiria, Leiria 2410-197, Portugal.
  • 2 University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.
  • 3 Pathology Department, Medical Faculty of University of Porto, Porto 4200-319, Portugal; Pathology Laboratory, Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP), Porto 4200-135, Portugal.
  • 4 Pathology Laboratory, Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP), Porto 4200-135, Portugal.
  • 5 University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal; Flow Cytometry Unit, Clinical Pathology Department, Unidade Local de Saúde de Coimbra, Coimbra 3000-075, Portugal; Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Ciências Biomédicas Laboratoriais, Coimbra 3046-854, Portugal.
  • 6 University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal; Department of Urology and Renal Transplantation, Unidade Local de Saúde de Coimbra, Coimbra 3000-075, Portugal.
  • 7 University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) Faculty of Medicine, Coimbra 3000-548, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology Consortium (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal. Electronic address: cgomes@fmed.uc.pt.
PMID: 40424822 DOI: 10.1016/j.biopha.2025.118188
Abstract

Immune checkpoint inhibitors have significantly improved advanced bladder Cancer care, but resistance remains a significant challenge. Adenosinergic signaling is an immunosuppressive mechanism hindered by tumor cells to escape from immune surveillance and suppress antitumor immune responses. Herein, we investigate whether co-targeting the adenosine pathway can modulate tumor immunity and enhance the efficacy of anti-PD-L1 therapy in an orthotopic murine bladder Cancer model. We observed higher expression of the ectonucleotidases CD39 and CD73 in tumor cells and CD4+ and CD8+ T cells within the tumor microenvironment and peripheral circulation and upregulation of the adenosine receptors A2A and A2B in tumor cells, further confirming the activation of the adenosinergic pathway in this murine model. CD39 inhibition demonstrated no therapeutic benefits nor synergistic effect with anti-PD-L1 immunotherapy in tumor-bearing mice. On the contrary, CD73 inhibition reduced tumor progression and synergized with anti-PD-L1, leading to complete remission in 38 % of cases and a significant reduction in tumor mass in the remainder compared to anti-PD-L1 monotherapy. This combination resulted in favorable systemic immune modulation, including increased circulating CD4+ and CD8+ T cells and a decreased neutrophil-to-lymphocyte ratio. These findings suggest that the adenosinergic pathway limits the efficacy of anti-PD-L1 immunotherapy in invasive bladder Cancer. Targeting the CD73 adenosinergic axis may enhance its effectiveness, offering a promising strategy to overcome resistance.

Keywords

Adenosinergic pathway; Bladder cancer; Ectonucleotidases; Immune checkpoint inhibitors; Immunotherapy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125286
    99.71%, CD73 Inhibitor