Non-immune microenvironmental cues driving melanoma local invasion, migration, and invasive phenotype switching

Melanoma remains the deadliest form of skin cancer and continues to account for a disproportionate number of deaths worldwide. Although targeted therapies have markedly improved outcomes for subsets of patients, both de novo and acquired resistance remain major clinical challenges, particularly in tumors with restricted systemic therapeutic options. Central to melanoma progression, invasion, and metastasis is the tumor microenvironment (TME), which engages in dynamic and reciprocal crosstalk with melanoma cells across all disease stages. Here, we synthesize recent advances elucidating how non-immune components of the melanoma TME (including keratinocytes, fibroblasts, extracellular matrix, and adipocytes) mechanistically regulate tumor motility and local invasion. We highlight how biochemical, biomechanical, and metabolic cues cooperatively remodel melanoma invasive behavior. Finally, we review current clinical efforts targeting melanoma-TME interactions and discuss critical gaps that must be addressed to advance these strategies into durable clinical therapies.