Metastatic melanoma presents clinical challenges due to tumor
heterogeneity and treatment resistance. Here, we report an integrative
workflow combining AI-based digital pathology with spatial proteomics to
support personalized treatment strategies in a case of a young patient
with recurrent melanoma and multiple metastases. Our AI model trained on
H&E images identified two spatially separated cell subpopulations
(PT1 and PT2) within the primary lesion, along with metastatic areas and
stromal components. MS-based proteomics was used to map the spatial
proteome across the clinically relevant regions. Our findings indicate
inter-tumor heterogeneity and increased kinases associated with
target-drug resistance. Convergent morphological and proteomic
signatures identified PT1 as an aggressive melanoma subtype and the
likely metastatic driver. Augmented glycolytic signaling and
mitochondrial metabolism were identified as drivers of melanoma
progression in this patient. Our findings suggest that targeted
therapies may provide limited benefit, while the combination with
metabolic inhibitors could represent a more effective treatment option
for the patient.