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A patient-specific lung tumoroid platform recapitulates tumor microenvironments for modeling in vitro therapeutic responses and immune-stromal interactions

ABSTRACT: Understanding tumor–stroma–immune interactions is crucial for overcoming resistance to chemo-immunotherapy in non-small cell lung cancer (NSCLC), yet modeling the tumor microenvironment (TME) ex vivo remains challenging. Here, we developed patient-specific lung cancer tumoroid (LCT) models integrating TME by reassembling lung cancer organoids (LCOs), cancer-associated fibroblasts (CAFs) and immune cells, which isolated and expanded from tumor tissues by using a modular Transwell-based culture system. LCTs retained major TME components and spatial organization of the primary tumor. The system supported high-fidelity pharmacologic screening, immune profiling, and mechanistic analysis of treatment-induced TME remodeling. Using LCTs, we observed tumor-intrinsic variation in immune engagement, CAF-mediated modulation, and an uncoupling between metabolic activation and immune stimulation. The LCT enables functional interrogation of patient-specific stromal–immune–tumor interactions, provides mechanistic insights into chemo-immunotherapy resistance, and offers a clinically relevant tool for precision immune-oncology and organoid-based therapeutic modeling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311792 | GEO | 2026/09/09

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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A patient-specific lung tumoroid platform recapitulates tumor microenvironments for modeling in vitro therapeutic responses and immune-stromal interactions

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