3 / 2026-01-15 10:10:36

A Longitudinal, Multi-omic Atlas Reveals the Emergence of a Spatially Organized Immunosuppressive Ecosystem in Resistant Melanoma

melanoma,immune checkpoint blockade,resistance,dynamic evolution

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Resistance to anti-PD-1 therapy remains a major clinical challenge in metastatic melanoma, yet the dynamic processes driving treatment failure are not fully understood. To address this, we generated a comprehensive longitudinal, multi-omic, and spatial atlas from 45 tumor samples collected at pre-, on-, and post-treatment time points across 10 patients. Our atlas suggests that resistance arises from evolving changes in the tumor microenvironment, culminating in the formation of an immunosuppressive ecosystem in non-responders. Critically, our data suggest that this resistant state is not defined by a single molecular event but by a distinct tumor architecture that facilitates immune exclusion. This architecture appears to be influenced by a specific malignant cell subgroup (c1), which alters the tumor microenvironment through dysregulated signaling pathways. We also identified recurring cellular neighborhoods (RCNs) enriched in extracellular matrix, which may form physical barriers to T-cell infiltration, potentially resulting in an “ignored-tumor” phenotype. Our work provides a comprehensive resource that underscores the significance of tumor architecture in resistance and proposes that overcoming therapeutic failure may require a dual strategy: targeting tumor-intrinsic PI3K/Akt signaling while simultaneously disrupting architectural barriers within the immunosuppressive ecosystem.