Introduction Melanoma is the deadliest skin cancer, with an increasing incidence especially in young adults. Melanoma may appear in nearly all pigmented animals. In the MeLiM minipig model, cutaneous melanomas develop during the perinatal period. They display many traits of malignancy as in humans. Intriguingly, MeLiM melanomas spontane-ously regress with a concomitant immune response. In other words, this cancer is totally "cured" within 6 months, with no side effect other than lesion and coat depigmentation. Compared to current immunotherapies, this model provides cues for cancer treatment with a high success rate and few adverse effects. Single-cell RNA-seq and spatial transcriptomics analysis could give indications on intratumor heterogeneity at the individual level, investigat-ing clonal evolution and the involvement of the microenvironment. Material and Methods Frozen samples spanning different time points during tumor evolution, from early lesions to progressive lesions sampled in couples of littermates were selected. Screening of conditions on nuclei isolation and purification for sin-gle-cell and depigmentation strategies for spatial analysis was achieved with RNA integrity and image analysis. Single-nucleus RNA-seq libraries and Visium transcriptomics were performed with the 10X Genomics technology. Results and Discussion We will present considerations for the best protocols adapted to our samples and a landscape of MeLiM lesions obtained after analysis of 61000 single cells. The analysis of cell types as cell cycle scores was consistent with immunofluorescence studies. Spatially resolved transcriptomics enabled to localize part of the cells identified in the single-cell libraries. Conclusions This study will help understand the regression mechanisms in MeLiM minipigs.