Inhibition of programmed cell death by melanoma cell subpopulations reveals mechanisms of melanoma metastasis and potential therapeutic targets.

Melanoma is an aggressive type of skin cancer that arises from melanocytes, the cells responsible for producing skin pigment. In contrast to non-melanoma skin cancers like basal cell carcinoma and squamous cell carcinoma, melanoma is more invasive. Melanoma was distinguished by its rapid progression, high metastatic potential, and significant resistance to conventional therapies. Although it accounted for a small proportion of skin cancer cases, melanoma accounts for the majority of deaths caused by skin cancer due to its ability to invade deep tissues, adapt to diverse microenvironments, and evade immune responses. These unique features highlighted the challenges of treating melanoma and underscored the importance of advanced tools, such as single-cell sequencing, to unravel its biology and develop personalized therapeutic strategies. Thus, we conducted a single-cell analysis of the cellular composition within melanoma tumor tissues and further subdivided melanoma cells into subpopulations. Through analyzing metabolic pathways, stemness genes, and transcription factors (TFs) among cells in different phases (G1, G2/M, and S) as well as between primary and metastatic foci cells, we investigated the specific mechanisms underlying melanoma metastasis. We also revisited the cellular stemness and temporal trajectories of melanoma cell subpopulations, identifying the core subpopulation as C0 SOD3 + Melanoma cells. Our findings revealed a close relationship between the pivotal C0 SOD3 + Melanoma cells subpopulation and oxidative pathways in metastatic tumor tissues. Additionally, we analyzed prognostically relevant differentially expressed genes (DEGs) within the C0 SOD3 + Melanoma cells subpopulation and built a predictive model associated with melanoma outcomes. We selected the gene IGF1 with the highest coefficient (coef) value for further analysis, and experimentally validated its essential function in the proliferation and invasive metastasis of melanoma. In immune infiltration analysis, we discovered the critical roles played by M1/M2 macrophages in melanoma progression and immune evasion. Furthermore, the development and progression of malignant melanoma were closely associated with various forms of programmed cell death (PCD), including apoptosis, autophagic cell death, ferroptosis, and pyroptosis. Melanoma cells often resisted cell death mechanisms, maintaining their growth by inhibiting apoptosis and evading autophagic cell death. Meanwhile, the induction of ferroptosis and pyroptosis was thought to trigger immune responses that helped suppress melanoma dissemination. A deeper understanding of the relationship between melanoma and PCD pathways provided a critical foundation for developing novel targeted therapies, with the potential to enhance melanoma treatment efficacy. These findings contributed to the development of novel prognostic models for melanoma and shed light on research directions concerning melanoma metastasis mechanisms and therapeutic targets.