Spatial organization of Lipid-associated TAMs in Tumor Microenvironment Drives Immune Exclusion and Checkpoint Therapy Resistance in Melanoma

Immune-checkpoint inhibitor (ICI) therapy has transformed melanoma treatment, yet many patients remain unresponsive or experience relapse. Using integrative bulk, single-cell, and spatial multi-omics profiling, we identified a subtype of tumor-associated macrophages (TAMs), known as lipid-associated TAMs (LA-TAMs). LA-TAMs share core lipid metabolic programs with adipose tissue-derived lipid-associated macrophages (LAMs), but they have distinct adaptation to glycolysis and β-oxidation in the hypoxic tumor microenvironment (TME). Spatial multi-omics analysis revealed distinct spatial architectures. In non-responders, LA-TAMs colocalized with sparsely distributed TIM3⁺ exhausted CD8⁺ T cells within an exclusionary TME. In contrast, the TME of responders displayed pronounced immune infiltration, with Interferon-primed TAMs (IFN-TAM) coinciding spatially with Granzyme B+ activated-CD8+ T cells. This suggests contrasting immune-neighborhoods linked to differential ICI-response. Importantly, the presence of LA-TAM neighborhoods emerged as the dominant determinant of poor ICI-therapy prognosis, outweighing the beneficial effects of IFN-TAM mediated immune activation. Patients harboring LA-TAM niches were consistently non-responders at baseline or progressed during follow-up. Together, these findings uncover the metabolic and spatial basis of macrophage heterogeneity in melanoma and position LA-TAM dominance as a key predictor and therapeutic vulnerability in ICI resistance.