Immune checkpoint inhibitors have transformed the treatment of advanced melanoma, yet many patients develop primary or acquired resistance. Although most work has focused on adaptive checkpoints (PD-1 and CTLA-4), accumulating evidence implicates innate immune suppression and stem-like, drug-resistant melanoma cell states. CD24, a small, heavily glycosylated glycosylphosphatidylinositol (GPI)-anchored surface protein, sits at the intersection of these processes and is emerging as a context-dependent biomarker and potential mediator of aggressive, therapy-resistant melanoma states. In this review, we synthesize evidence indicating that CD24 is both a tumour-intrinsic and tumour-extrinsic regulator in melanoma. We summarize the structure, glycosylation and regulation of CD24, then discuss its role in melanoma, supporting phenotypic plasticity, sustaining stem-like populations and promoting resistance to BRAF-targeted and cytotoxic therapies through SOX2/STAT3-linked programmes. We then examine the CD24-Siglec-10 axis as an innate immune checkpoint that suppresses macrophage and dendritic cell function, promotes immune-excluded 'cold' tumour microenvironments and may shape responses to immunotherapy among CD24+ melanoma cells. We highlight CD24 in tumour tissue, blood and extracellular vesicles as potential biomarkers of prognosis and pathway activity, and review CD24-axis interventions, including anti-CD24 antibodies, Siglec-10 antagonists and CD24-targeted CAR-T/CAR-NK cells, with rational combinations alongside PD-1/CTLA-4 blockade and MAPK-targeted therapy. We propose that biomarker-driven trials targeting this axis could open a new front in melanoma immunotherapy.
Lasalle et al. (2026) studied this question.