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Low pH, High Stakes: A Narrative Review Exploring the Acid-Sensing GPR65 Pathway as a Novel Approach in Renal Cell Carcinoma
by
, , ,
Michael Grant
1,2,*, 
Barbara Cipriani
3,
Alastair Corbin
3,
David Miller
3,
Alan Naylor
3,
Stuart Hughes
3,
Tom McCarthy
3,
Sumeet Ambarkhane
3,
Danish Memon
4,
Michael Millward
5,
Sumanta Pal
6 and
Ignacio Melero
7 1
St Bartholomew’s Hospital, London EC1A 7BE, UK
2
Weatherden Limited, London WC1V 6DF, UK
3
Pathios Therapeutics Limited, Oxford OX2 6HJ, UK
4
Molecule to Medicine, Oxford OX1 4PS, UK
5
School of Medicine, University of Western Australia and Linear Clinical Research, Perth, WA 6009, Australia
6
City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA
7
Clinica Universidad de Navarra, 31008 Pamplona, Spain
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(23), 3883; https://doi.org/10.3390/cancers17233883 (registering DOI)
Submission received: 30 October 2025
/
Revised: 16 November 2025
/
Accepted: 20 November 2025
/
Published: 4 December 2025
(This article belongs to the Special Issue Understanding the Molecular Basis and Immunobiology of Renal Cell Carcinoma and Exploring Novel Therapeutic Strategies)
Simple Summary
Renal cell carcinoma is a type of kidney cancer that remains difficult to treat, even with modern immunotherapy and targeted drugs. One important reason for treatment failure is that these tumours create an unusually acidic environ-ment around themselves. This acidic setting weakens the body’s immune cells, helps cancer cells avoid detection, and makes therapies less effective. Recent research has identified a sensor on immune cells, called GPR65, that becomes activated in acidic conditions and contributes to this immune suppression. Blocking GPR65 has been shown in early laboratory studies to restore the ability of immune cells to recognise and attack cancer. New medicines that target this pathway are now being tested in clinical trials. This research aims to understand how targeting acidity-sensing mech-anisms could improve responses to immunotherapy and lead to more effective treatments for people with kidney cancer.
Abstract
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.
