Deciphering the crosstalk between cancer stemness and the immune microenvironment in melanoma

BACKGROUNDTumor stemness fuels cutaneous melanoma (CM) progression and therapeutic resistance, posing a major challenge in clinical management. However, the spatial architecture of the stem cell niche and the causal genetic drivers orchestrating its maintenance remain elusive.

METHODSWe employed an integrative multi-omics framework combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to map the melanoma stem-like cell (CSC) ecosystem. Computational algorithms, including CytoTRACE (for cellular differentiation inference) and hdWGCNA (for spatial gene network detection), were leveraged to delineate stemness trajectories and their spatially co-localized modules. Furthermore, Mendelian Randomization (MR), a genetic epidemiology method, was applied to evaluate the potential causal roles of candidate genes, thereby moving beyond observational correlations. These findings were validated through immune landscape profiling and pharmacogenomic sensitivity analysis.

RESULTSWe identified a stem-like subpopulation confined within a distinct hypoxic niche. MR analysis identified IGFBP7, LGALS1, and RPL10A as potential causal drivers of CM. Mechanistically, we reveal a dual mode of maintenance, IGFBP7 and LGALS1 act extrinsically to construct immune-excluded microenvironments via vascular remodeling and myeloid barriers, whereas RPL10A functions intrinsically to secure biosynthetic capacity via enhanced translation. Pharmacogenomic profiling further supports a mechanism-based therapeutic stratification, revealing subtype-specific vulnerabilities to MAPK inhibitors, taxanes, and platinum agents.

CONCLUSIONBy defining the causal spatial architecture of melanoma stemness, this study provides a translational rationale for biomarker-driven patient stratification and mechanism-based therapeutic selection, offering specific strategies to disrupt the CSC niche and overcome therapeutic resistance.

Abstract from PubMed