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High-resolution and noninvasive profiling of the tumor microenvironment with spatial ecotypes [Visium]

ABSTRACT: Multicellular programs in the tumor microenvironment (TME) drive cancer pathogenesis and response to therapy but remain challenging to identify and profile clinically. Here, we present a machine learning framework for multi-analyte profiling of spatially dependent cell states and multicellular ecosystems, termed spatial ecotypes (SEs). By integrating 10M single-cell and spot-level spatial transcriptomes from diverse human carcinomas and melanomas, we identified nine SEs with broad conservation—each with unique biology, geospatial features, and clinical outcome associations, including several linked to immunotherapy response. Notably, SEs were distinguishable by DNA methylation profiling and recoverable from plasma cell-free DNA (cfDNA) using deep learning. In cfDNA from nearly 100 melanoma patients, SE levels exhibited striking associations with immunotherapy response. Our data reveal fundamental units of TME organization and demonstrate a multimodal platform for solid and liquid TME profiling, with implications for improved risk stratification and therapy personalization.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320041 | GEO | 2026/05/07

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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High-resolution and noninvasive profiling of the tumor microenvironment with spatial ecotypes [Visium]

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