Melanoma is an aggressive skin cancer with a high potential for metastasis, particularly to the lungs. This study aimed to investigate how secretions by human pulmonary microvascular endothelial cells (HPMECs) affect the invasiveness of melanoma cells and to identify associated changes in cytokine and chemokine receptor gene expression. Two melanoma cell lines (WM3248 and WM902B), representing different levels of baseline invasiveness, were used in Matrigel invasion assays with HPMEC-conditioned medium as the chemoattractant. Both cell lines exhibited significantly increased invasion in response to HPMEC-CM compared to control medium supplemented with 10% fetal bovine serum (p = 0.037). Gene expression analysis using a qRT-PCR targeting 88 cytokine receptor genes revealed upregulation of multiple receptors in both invasive cell lines, including IL6ST, IL13RA1, IL10RA, and CCR4 which have known functions associated with immune modulation and metastatic behavior. Our findings support our hypothesis that the lung microenvironment actively promotes melanoma cell invasion through cytokine signaling and identify potential molecular targets for preventing or reducing pulmonary metastasis in melanoma patients.