The function and subcellular localization of programmed cell death 4 (PDCD4) in melanoma remain poorly characterized. Previous work suggests PDCD4 interacts with Pleckstrin Homology Domain Containing A5 (PLEKHA5), influencing survival in patients with melanoma brain metastases. Here, we investigated the distribution of PDCD4 within tumor cells and the surrounding microenvironment and examined its association with clinical outcomes. Using quantitative immunofluorescence on tissue microarrays with comprehensive clinicopathological annotations, combined with single-cell RNA sequencing of a brain metastasis, we profiled PDCD4-positive immune cell populations. Our results reveal stage-specific changes in PDCD4 expression, with higher levels in tumors and stroma linked to improved survival in primary melanomas and intracranial metastases, but not in extracranial metastatic lesions. Beyond its known expression on CD8+ T cells and natural killer cells, PDCD4 was also present on B cells and mast cells. Elevated PDCD4 within the tumor microenvironment correlated with increased immune infiltration. These findings highlight the potential importance of the PDCD4–PLEKHA5 axis in melanoma brain metastasis and support further exploration of this pathway as a therapeutic target.
