First Blood Test to Map the Tumor Microenvironment Unveiled by Stanford and Mayo Clinic Researchers
Key Insights
Researchers from Stanford Medicine and Mayo Clinic developed the first blood test capable of noninvasively profiling the tumor microenvironment, published in Nature.
The test uses AI-powered analysis of methylation patterns on cell-free DNA to identify nine distinct "spatial ecotypes" that predict immunotherapy response.
In studies involving over 1,300 patients across melanoma (search), lung, bladder, and gastric cancers, specific ecotypes strongly correlated with treatment outcomes and survival.
A landmark study published in Nature describes the first blood test capable of mapping the complex ecosystem surrounding cancer cells—the tumor microenvironment (TME)—offering a transformative approach to predicting which patients will benefit from immunotherapy. The work, led by researchers at Stanford Medicine and Mayo Clinic, represents what co-senior author Aadel Chaudhuri, M.D., Ph.D., professor of radiation oncology at Mayo Clinic, calls "a complete paradigm shift."
"Until now, liquid biopsies or blood tests have focused almost entirely on tumor cells. For the first time, we can use a simple blood test to understand the tumor's microenvironment, which is critical for determining how patients respond to modern cancer therapies," said Dr. Chaudhuri.
From Spatial Transcriptomics to Nine Conserved Ecotypes
The research team began by analyzing tumor samples using spatial transcriptomics, an advanced technique that maps how different cells interact within a tumor. This massive undertaking involved 10 million single-cell RNA sequencing across 10 cancer types. Through machine learning, the team identified nine distinct cellular neighborhoods, termed "spatial ecotypes" (SEs), each representing a unique immune and stromal environment.
These nine neighborhoods are conserved across all 17 cancer types tested and exhibit strikingly different biological characteristics. SE4, for instance, represents an environment where the immune system is asleep and hypoxic. SE7 and SE8 are "war zones" rich with immune cells—hot tumors. SE5 exhibits intense immunosuppression, hostile to the immune system and portending poor survival. SE9 resides deep in the tumor core, driving angiogenesis.
"Almost like geographic mapping, we were able to map where in the tumor microenvironment these neighborhoods of co-associated cells live," Dr. Chaudhuri explained. Some ecotypes are more likely to occur at the border of the tumor and healthy tissue, while others are found deeper inside.
AI-Powered Translation to a Blood Test
To translate these spatial insights into a clinically accessible format, the team collaborated with Aaron Newman, Ph.D., associate professor of biomedical data science at Stanford Medicine and co-senior author of the study. Newman's team developed an artificial intelligence framework—the Liquid Ecotyper—that detects these spatial ecotypes from blood samples.
The test leverages methylation patterns—chemical markings on DNA that help control gene activity—on cell-free DNA shed by tumors into the bloodstream. This approach provides cell identity from DNA fragments leaked into the blood, akin to wastewater surveillance for infectious disease detection. "This is the first time we've been able to noninvasively profile the tumor microenvironment at this level," said Dr. Chaudhuri.
Clinical Validation Across Multiple Cancers
The Liquid Ecotyper was validated in 78 patients with malignant melanoma (search) pre-treatment from Yale University. Patients with SE7/8 ecotypes benefited from immune checkpoint therapy, while those with SE4 resisted treatment and had shorter survival—findings that matched tissue biopsy results.
In broader studies involving more than 1,300 patients across multiple cancers including melanoma (search), lung, bladder, and gastric cancers, specific spatial ecotypes were strongly associated with treatment outcomes. Standard biomarkers, such as tumor mutation burden and PD-L1 (search) levels, showed inferior predictive power.
Real-Time Monitoring and Treatment Guidance
Because the test is blood-based, it enables serial monitoring of how a patient's tumor microenvironment evolves during treatment. Early data indicate that changes in spatial ecotypes can signal treatment response or resistance months before traditional imaging can detect changes.
"If a patient isn't going to respond, that's time we could be using a different treatment," Dr. Chaudhuri noted. "Better upfront decision-making can directly improve outcomes."
Importantly, identifying likely resistance to immunotherapy may guide patients toward alternative treatments better suited to their tumor biology, informed by their personalized spatial ecotype profile.
Beyond Immunotherapy and Beyond Cancer
While the published study focused primarily on melanoma (search), ongoing work extends to lung cancer (search), bladder cancer (search), mesothelioma (search), and response to other therapies including CAR T and bispecific antibodies. The research team has new data beyond the published study showing the ability to predict complete responses to antibody-drug conjugate (ADC)-based combination therapy.
"This is not just about cancer," Dr. Chaudhuri said. "It could provide insights into a wide range of diseases by helping us understand complex biological environments in the body."
A company, Liquid Cell Dx (search), has been founded to make the TME blood test commercially available, though it may become accessible sooner through the academic centers involved in the current study. Further studies are underway to validate the test in larger patient populations and move it into clinical use.