Collectively, our data indicate that the inhibition of RAS/RAF/PI3K-mediated pathways, as observed with RGS treatment, directly induce CD40 expression in melanoma cells to trigger immunogenic cell death, which is associated with increased expression of co-stimulatory signals (e.g., CD40, CD80, and ICOS-L) for mediating anti-tumor responses. Here, CD40 is linked to melanoma.