We show that 50% of BRAFV600E-mutant melanomas express TNFR2, that co-expression of TNFR1 and TNFR2 on these tumors is required for solTNF-mediated induction of MAPKi resistance and that selective neutralization of solTNF can mitigate solTNF-mediated MAPKi resistance. Here, TNFRSF1B is linked to melanoma.