Advanced 3D Spatial Mapping of Tumor Microenvironments Uncovers New Targets for Personalized Cancer Therapy

Researchers at the Max Delbrück Center for Molecular Medicine, led by Professor Nikolaus Rajewsky, have developed a cutting-edge method to map tumor cell neighborhoods in three dimensions, revealing promising targets for individualized cancer treatments. Using high-resolution spatial transcriptomics combined with extracellular matrix imaging, the team analyzed an early-stage lung tumor in unprecedented detail. This approach uncovered how tumor cells interact with surrounding immune and stromal cells, highlighting specific molecular pathways that could be targeted to halt tumor progression.

The study employed novel computational algorithms, notably STIM, to reconstruct 3D models of tumor tissues from datasets initially acquired as 2D spatial transcriptomics. The team accessed the NanoString CosMx platform, capable of detecting over a thousand RNA molecules simultaneously across 340,000 individual cells, allowing for precise identification of 18 distinct cell types within the tumor. By integrating imaging techniques like second harmonic generation, the researchers characterized the extracellular matrix components—identifying regions rich in elastin versus collagen—providing insight into tissue health and remodeling.

A significant breakthrough was understanding how tumor cells manipulate their microenvironment. For instance, activated fibroblasts and collagen-rich areas support tumor growth, while immune cells are often blocked from infiltrating the tumor due to immune suppression mechanisms. The researchers could observe cell-to-cell communications, such as how tumor cells hinder immune cell entry, suggesting that immunotherapies like immune checkpoint inhibitors might be effective by reversing such suppression.

Remarkably, this methodology can extract comprehensive molecular information from standard clinical tissue samples, including archived paraffin-embedded specimens. This paves the way for pathology 2.0—integrating molecular and spatial data into routine diagnostics. The team plans to expand their study to a larger cohort of 700 samples from 200 patients, aiming to refine personalized treatment strategies and combine spatial transcriptomics with protein activity analyses.

This innovative approach marks a substantial advancement in cancer research, enabling detailed visualization of tumor ecosystems in 3D, ultimately guiding more precise and effective therapies for patients. Their findings are published in the journal Cell Systems.

For more information, see the publication: Tancredi Massimo Pentimalli et al, "Combining spatial transcriptomics and ECM imaging in 3D for mapping cellular interactions in the tumor microenvironment," Cell Systems (2025).