Low pH, High Stakes: A Narrative Review Exploring the Acid-Sensing GPR65 Pathway as a Novel Approach in Renal Cell Carcinoma
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Le résumé fourni par la source
Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy accounting for 3% of adult cancers globally. Despite advances in immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF)-targeted therapies, durable disease control remains elusive for many patients. Increasing evidence implicates the acidic tumour microenvironment (TME) as a critical mediator of RCC progression, immune evasion, and therapeutic resistance. Solid tumours, including RCC, exhibit reversed pH gradients, characterised by acidic extracellular (pH 6.2-6.9) and alkaline intracellular conditions. This dysregulation arises from enhanced glycolysis, hypoxia-driven lactate accumulation, and the overexpression of pH-regulating enzymes such as carbonic anhydrase (CA9). Acidic TMEs impair cytotoxic T-cell and NK-cell activity, promote tumour-associated macrophage (TAM) polarisation towards an immunosuppressive phenotype, and upregulate alternative immune checkpoints. These mechanisms collectively undermine ICI efficacy and contribute to primary and secondary treatment resistance. Proton-sensing G-protein-coupled receptors (GPCRs), notably GPR65, have emerged as pivotal mediators linking extracellular acidosis to immune dysfunction. Preclinical studies demonstrate that GPR65 antagonists restore anti-tumour immune activity by reversing acidosis-driven immunosuppression and enhancing antigen processing. In RCC models, selective GPR65 inhibitors have shown the ability to reduce immunosuppressive cytokine IL-10 production, induce immunoproteasome activation, and synergise with anti-PD-1 therapy. The first-in-class GPR65 inhibitor, PTT-4256, is now under evaluation in the Phase I/II RAISIC-1 trial (NCT06634849) in solid tumours, including RCC. Targeting acid-sensing pathways represents a novel and promising therapeutic strategy in RCC, aiming to remodel the TME and overcome ICI resistance. Integrating GPR65 inhibition with existing immunotherapies may define the next era of RCC management, warranting continued translational and clinical investigation.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Low pH, High Stakes: A Narrative Review Exploring the Acid-Sensing GPR65 Pathway as a Novel Approach in Renal Cell Carcinoma
- Date Crossref
- 04/12/2025
- Éditeur
- MDPI AG
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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St Bartholomew's Hospital pays non établi dans la noticeÉtablissement de santé
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Weatherford (United Kingdom) pays non établi dans la noticeEntreprise
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e-Therapeutics (United Kingdom) pays non établi dans la noticeEntreprise
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Science Oxford pays non établi dans la noticeOrganisation à but non lucratif
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Linear Clinical Research pays non établi dans la noticeStructure de recherche
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City of Hope pays non établi dans la noticeÉtablissement de santé
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Clinica Universidad de Navarra Department of Immunology and Immunotherapy pays non établi dans la noticeÉtablissement de santé
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Weatherden Limited pays non établi dans la noticeInstitution
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Pathios Therapeutics Limited pays non établi dans la noticeInstitution
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Molecule to Medicine pays non établi dans la noticeInstitution
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St Bartholomew's Hospital, Weatherford (United Kingdom) et e-Therapeutics (United Kingdom), avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.