Cellular and spatial continuum of TAM functional states governs immune exclusion and dictates immune checkpoint resistance in melanoma.

Lipid-associated TAMs (LA-TAMs) define a macrophage-centered immune neighborhood in melanoma that predicts poor ICI response and survival, linked to immune-excluded architecture.

• Why it matters: Many melanoma patients fail to respond or develop resistance to immune checkpoint inhibitors, but the cellular and spatial TME features driving these outcomes are not well resolved.
• What they did: The study integrated public scRNA-seq (N=32) with in-house spatial transcriptomics and imaging mass cytometry (N=6) and validated using a scRNA-seq signature-matrix deconvolution of bulk RNA-seq (N=334), plus Kaplan-Meier, Cox models, and machine learning.
• The result: In non-responders, LA-TAMs colocalized with sparsely distributed TIM3a exhausted CD8a T cells in immune-excluded TME, whereas responders showed IFN-TAMs associated with Granzyme Ba activated CD8a T cells; LA-TAM abundance robustly predicted poor response and survival.

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