Melanoma, like other cancers, originates from a single clone. As the cancer progresses, the tumor thickens and immune evasion ensues. However, few studies have investigated the mechanisms involved in these processes using spatial transcriptomics. We aimed to elucidate genetic and transcriptional heterogeneity in relation to melanoma thickness and to explore the molecular mechanisms related to immune escape. Five punch-biopsied fresh tissue samples and saliva were obtained from a single patient and used for paired whole exome sequencing. The subsequent excision specimen was prepared for formalin-fixed paraffin-embedded block and profiled using spatial transcriptomics. DNA-level mutation accumulation was commensurate with the thickness of the melanoma. Spatial transcriptome analysis indicated that immune evasion involves changes in antigen presentation as well as defects in β2-microglobulin and human leukocyte antigen class I processing. Levels of these molecules, which are critical for T cell recognition of tumor antigens, tended to significantly decrease as the melanoma depth increased. We also found that the expression of caspases and interferon alpha inducible protein-encoding genes inversely correlated with tumor thickness. The study was based on sampling a lesion from a single patient. Spatial transcriptomics can increase our mechanistic understanding of tumor immune escape.