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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. View Publication

Cell surface proteins offer significant cancer therapeutic potential attributable to their accessible membrane localization and central roles in cellular signaling,yet their promise remains largely untapped due to technical challenges inherent to profiling them. Here,we employ N-glycoproteomics to analyze 85 patient-derived xenografts (PDXs),constructing Glyco PDXplorer—an in vivo pan-cancer atlas of cancer-derived surface proteins. We develop a target discovery pipeline to prioritize proteins with favorable expression profiles for immunotherapeutic targeting and validate FAT2 as a squamous-cancer-enriched surface protein minimally detected in normal tissue. Functional studies reveal that FAT2 is essential for head and neck squamous cancer (HNSC) cell growth and adhesion through regulation of surface architecture and integrin-PI3K signaling. Chimeric antigen receptor (CAR)-T cells targeting FAT2 demonstrate anti-tumor activity. This work lays the foundation for developing FAT2-targeted therapies and represents a pivotal platform to inform therapeutic target discovery across cancers. Graphical abstract Highlights•Pan-cancer landscape of cancer-derived cell surface proteins detected in vivo•Discovery pipeline to prioritize proteins as immunotherapy target candidates•Validation of FAT2 as an SCC surface protein with minimal normal tissue expression•FAT2 CAR-T cells demonstrate anti-tumor activity in pre-clinical models Govindarajan et al. leverage N-glycoproteomics and PDX models to decode the in vivo cancer cell surfaceome and establish Glyco PDXplorer—a target discovery platform. The identification and validation of FAT2 as a previously undescribed,actionable antigen demonstrates the utility of Glyco PDXplorer for uncovering therapeutic vulnerabilities. View Publication