Melanosomes Act as Decoys to Evade Immunosurveillance of Melanoma

Melanomas arise from melanocytes within the skin, a specialized cell type that synthesizes and packages pigment in the form of melanin, and this pigment is transported to neighboring cells in large extracellular vesicles known as melanosomes. Previous studies have provided evidence that melanosomes play an important role not only in normal physiology but also in melanoma, as melanoma-derived melanosomes have been shown to reprogram neighboring immune and stromal cells and contribute to drug resistance. However, whether tumor-derived melanosomes directly affect immune function remains an open question. Chemla, Itzhaki, Melamed, Weller, Sade, Manich, Reshef, Xenidis, Maliah, and colleagues assessed metastasis samples from patients with melanoma and found that those who responded poorly to immunotherapy harbored a higher number of T cells loaded with pigment, suggesting that melanosomes may be directly interacting with T cells and impairing their function. Indeed, the addition of melanosomes to in vitro coculture of antigen-specific murine CD8+ T cells with cognate antigen-expressing melanoma cells substantially reduced T cell cytotoxicity. Moreover, in an in vivo mouse model of melanoma, administration of kojic acid, which blocks pigment synthesis and subsequent melanosome secretion, markedly reduced tumor growth, prolonged survival, and increased CD8+ T-cell infiltration. Isolation of melanosomes from murine and patient samples revealed that melanosomes express MHC class I molecules, and MHC immunopeptidomic analyses provided further evidence that melanosomes present tumor-associated antigens on these MHC class I molecules that can then be recognized by infiltrating CD8+ T cells. The T cell receptor (TCR) repertoire was common between infiltrating lymphocytes that recognized tumor cells versus melanosomes, suggesting that melanosomes might function as a decoy to sequester antigen-specific T cells and prevent melanoma immunosurveillance. Notably, transcriptional analysis of T cells following exposure to antigen-presenting melanosomes demonstrated that melanosome engagement induced suboptimal TCR signaling and mitochondrial activity, with T-cell apoptosis occurring after longer exposures. While this dysfunctional T-cell state warrants further investigation, these findings highlight a previously unappreciated role of melanosomes in directly hindering cytotoxic T-cell function and propose that targeting melanosome release may be a therapeutic strategy for melanoma.Chemla Y, Itzhaki O, Melamed S, Weller C, Sade Y, Manich P, et al. HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion. Cell 2025;189:233–51.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online athttps://aacrjournals.org/cdnews.