# Rewiring melanoma cell fate: TRPM8 modulators trigger apoptosis and boost NK cell cytotoxicity

## TL;DR

This study shows that targeting the TRPM8 ion channel in melanoma cells can trigger cell death and enhance immune cell attack, offering a potential new treatment strategy.

## Contribution

The study introduces TRPM8 as a novel therapeutic target in melanoma by demonstrating its role in inducing apoptosis and boosting NK cell activity.

## Key findings

- TRPM8 is overexpressed in metastatic melanoma compared to normal cells.
- TRPM8 inhibition induces calcium-independent mitochondrial apoptosis and increases NK cell-mediated cytotoxicity via ULBP1 upregulation.
- TRPM8 targeting activates the ATM/p53 pathway and pro-apoptotic proteins.

## Abstract

Metastatic melanoma is an aggressive malignancy with limited long-term treatment success due to therapeutic resistance and immune evasion. The transient receptor potential melastatin 8 (TRPM8) ion channel is overexpressed in melanoma but its role as therapeutic target remains unexplored. We investigated the anti-tumor effects of novel TRPM8 modulators in metastatic melanoma cells using viability assays, apoptosis markers, mitochondrial function analyses, reactive oxygen species (ROS) measurements and gene silencing. Their functional impact was further assessed in 3D melanoma organoids, clonogenic survival assays, and natural killer (NK) cell co-culture systems. TRPM8 is significantly overexpressed in metastatic melanoma, as compared with the normal counterparts. Its pharmacological inhibition with novel modulators selectively induces calcium-independent mitochondrial apoptosis characterized by ROS accumulation, mitochondrial membrane depolarization, cytochrome c release, and caspase-3 activation. This process involves activation of the ATM/p53 pathway and upregulation of pro-apoptotic proteins. Additionally, TRPM8 modulators increase expression of the NK cell-activating ligand ULBP1, enhancing melanoma susceptibility to NK-mediated cytotoxicity. Our study identifies TRPM8 as a promising biomarker in melanoma. Its targeting triggers mitochondrial cell death and simultaneously boosts NK cell recognition via ULBP1/NKG2D engagement. TRPM8 targeting in combination with immunotherapy might be, hence, further explored in clinical setting of advanced melanoma.