Modulation of Spliceosomal Protein hnRNPH2 Increases Melanoma Cell Pro-Inflammatory Signaling <em>In Vitro</em>

Melanoma is the most aggressive and deadliest form of skin cancer, and the current treatments of mel-anoma have many limitations, which necessitates discovering new compounds and targets for melanoma. Two probes, 2155-14 and 2155-18, were identified to induce apoptotic cell death, autophagy, and immune signaling modulation through hnRNPH1/H2-dependent mechanisms. RNA sequencing following the siRNA-mediated knockdown of hnRNPH1/H2 in melanoma cells revealed an enrichment of im-mune-related signaling pathways. The present study investigated the effect of genetic and pharmacologic downregulation of hnRNPH1/H2 on melanoma immunogenicity in vitro. Our results indicate that treating melanoma cell lines with 2155-14, 2155-18, or hnRNPH2 siRNA led to hnRNPH1/H2 downregulation. This resulted in a significant upregulation of pro-inflammatory pathways and simultaneous downregulation of anti-inflammatory pathways. These findings provide the first insight into the role of hnRNPH1/H2 as critical drivers of melanoma immunogenicity and suggest their potential as novel therapeutic targets for enhancing melanoma treatment outcomes. This study underscores the impact of post-transcriptional regulation on the immune environment in melanoma and in cancer in general.