# GPR65

Source: https://onco.cc/targets/gpr65/  
OnCo record `gpr65` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

GPR65 is a sensor on immune cells that detects acidity. Tumours are often acidic, and the idea behind blocking GPR65 is to stop that acidity from turning nearby immune cells into ones that help the tumour; a GPR65 inhibitor is in an early trial.

## Summary

GPR65 (chromosome 14q31.3) is a proton-sensing G protein-coupled receptor activated by extracellular pH, mainly coupled to G(s) and adenylate cyclase (UniProt Q8IYL9); it is expressed predominantly in immune cells (doi:10.1016/j.bbadis.2021.166288). A 2013 review in Frontiers in Physiology describes the tumour microenvironment as acidic because of glycolytic metabolism, hypoxia and poor perfusion, and the pH-sensing receptors GPR4, GPR65, GPR68 and GPR132 as regulators of cancer cell spread, immune cell function, inflammation and blood vessel formation (Justus et al., doi:10.3389/fphys.2013.00354). In OnCo, PTT-4256 is an oral GPR65 inhibitor; its developer's case is that tumour acidity acts through GPR65 to switch immune cells into a suppressed, pro-tumour state.

## Fields

- Kind: Target
- Last checked: 2026-11-03
- Also known as: G protein-coupled receptor 65; TDAG8
- Tags: pipeline-gap-target
- Symbol: GPR65
- Class: other
- Biology: Proton-sensing receptor (also called TDAG8) that signals through G(s) and cyclic AMP; it may also bind the glycosphingolipid psychosine (UniProt Q8IYL9).
- Where found: Immune cells in acidic tumour regions (doi:10.3389/fphys.2013.00354); Advanced solid tumours (PTT-4256 trial)

## Notes

- Prevalence not recorded: HGNC, UniProt and the paper cited give no positivity rate.

## Sources

- HGNC HGNC:4517: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:4517
- UniProt Q8IYL9: https://www.uniprot.org/uniprotkb/Q8IYL9/entry
- NCBI Gene 8477: https://www.ncbi.nlm.nih.gov/gene/8477
- Acidic tumor microenvironment and pH-sensing G protein-coupled receptors (Front Physiol 2013): https://doi.org/10.3389/fphys.2013.00354
- GPR65 (TDAG8) in intestinal inflammation and colitis-associated colorectal cancer (BBA Mol Basis Dis 2022): https://doi.org/10.1016/j.bbadis.2021.166288

## Connected records

- cancers: [Metastatic cancer (cancer that has spread)](https://onco.cc/cancers/metastatic-cancer/)
- drugs: [PTT-4256](https://onco.cc/drugs/ptt-4256/)

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