Aligned with evidence that aged skin fibroblasts stimulate melanoma invasion, metastasis, and resistance to BRAFi via increased secretion of SFRP2 into the TME (4, 6, 78, 79), our data suggest that aged tumors were less likely to benefit from BRAFi + MEKi therapy, given their high levels of NR2F1, which cooperated with the aged TME to drive drug tolerance. Here, SFRP2 is linked to melanoma.