Sustained Galiellalactone treatment breaks the metastatic resilience of BRAF-inhibitor-resistant melanoma cells.

STAT3 hyperactivation in metastatic and therapy-resistant melanoma drives tumorigenesis and immunotherapy resistance by promoting tumor-stromal interactions, making its inhibition a crucial therapeutic strategy. Interestingly, synthetic STAT3 inhibitors could not manage to enter clinical trials due to their short half-lives, poor bioavailability and non-specific effects. Here, we have shown that Galiellalactone, a natural, irreversible STAT3 inhibitor, blocks IL-6 and WNT5A-mediated STAT3 Phosphorylation and migration in BRAF-inhibitor (BRAFi)-sensitive melanoma cells. Galiellalactone treatment leads to prolonged STAT3 inhibition, which obstructs both metastatic functions and secretome-mediated paracrine interactions in both BRAFi-sensitive and resistant melanoma cells, via the reduction of MCAM and N-cadherin protein expression. Altogether, our findings support that Galiellalactone is a potential inhibitor that could block the metastatic function of drug-resistant melanoma cells and also obstruct the possible paracrine activation of STAT3 conferred by stromal cells present in the tumor microenvironment.