Mayo Clinic and Stanford researchers develop first blood test to map tumor “neighborhoods,” improving prediction of therapy response

ROCHESTER, Minn. — Mayo Clinic and Stanford Medicine researchers have developed the first blood test to map the complex ecosystem surrounding cancer cells, offering a more accurate way to predict which patients will benefit from immunotherapy. Their study's findings, published in Nature, represent a major advance in precision oncology and could help guide treatment decisions across multiple cancer types and treatments.

"This is a complete paradigm shift," says Aadel Chaudhuri, M.D., Ph.D., professor of radiation oncology at Mayo Clinic and co-senior author of the study. "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."

Capturing and mapping the tumor environment

Immunotherapy has transformed cancer care, but only for some patients. Current tools used to predict tumor response, such as testing for the number of DNA mutations in a tumor and the levels of certain proteins on a cancer cell, aren't able to capture the level of detail needed.  

"One of the challenges is that these existing methods only have modest associations," Dr. Chaudhuri says. "They're essentially 'surrogates of surrogates' and don't fully capture what's happening inside the tumor environment."

To address this gap, the research team posed the question: Can a better readout of the tumor microenvironment be developed from a liquid biopsy of a patient's blood?

To start their investigation, they turned to spatial transcriptomics, an advanced technique that maps how different cells interact within a tumor. By analyzing tumor samples, they identified nine distinct cellular neighborhoods, or spatial ecotypes, each representing a unique immune and stromal (the noncancerous cells and structures surrounding the tumor) environment.

"Almost like geographic mapping, we were able to map where in the tumor microenvironment these neighborhoods of co-associated cells live," Dr. Chaudhuri explains. All 17 tested cancer types share these neighborhoods; some are more likely to occur at the border of the tumor and healthy tissue, while others were more likely found deeper inside the tumor. "Then, we showed that certain neighborhoods, or spatial ecotypes, are associated with survival and immunotherapy response outcomes."

Using AI to develop a simple blood test

To identify these tumor neighborhoods, 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 methods to define these neighborhoods from tumor samples and an artificial intelligence (AI) framework to detect them in blood.

Using methylation — chemical markings on DNA that help control gene activity — on cell-free DNA shed by tumors into the bloodstream, the researchers created a liquid biopsy test that details the tumor microenvironment beyond its cancer cells. This means a blood draw, not an incision, is all it takes to profile the tumor's spatial ecotypes.

"This is the first time we've been able to noninvasively profile the tumor microenvironment at this level," says Dr. Chaudhuri.

In studies involving more than 1,300 patients across multiple cancers, including melanoma, lung, bladder and gastric cancers, specific spatial ecotypes were strongly associated with treatment outcomes. Certain ecotypes are predicted to respond positively to immunotherapy, while others were linked to treatment resistance and poorer survival. Standard biomarkers showed inferior predictive power.

Improving treatment decisions and avoiding side effects

The ability to predict immunotherapy response before starting treatment could have an immediate clinical impact.

Cancer therapy can be time-consuming and carry significant side effects. Identifying patients unlikely to benefit from immunotherapy could allow clinicians to choose more effective alternate therapies sooner.

"If a patient isn't going to respond, that's time we could be using a different treatment," Dr. Chaudhuri says. "Better upfront decision-making can directly improve outcomes."

Importantly, finding likely resistance to an immunotherapy is not necessarily bad news. It may help guide patients toward different treatments better suited to their tumor biology, further guided by the patient's personalized spatial ecotype profile.

Tracking cancer progress in real time

Because the test is blood-based, it also opens the door to ongoing monitoring of how a patient's tumor microenvironment evolves during treatment.

In early data, researchers observed that changes in spatial ecotypes could signal treatment response or resistance months before traditional imaging can.

"This gives us a window into how the tumor microenvironment is changing over time," says Dr. Chaudhuri. "We've never been able to see that before in a practical way."

Broadening the approach across cancers and other diseases

While the initial study focused primarily on patients with melanoma, the approach shows promise across many cancers, including lung cancer and bladder cancer, where treatment decisions are complex and time sensitive. 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. Researchers also believe the technology-assisted approach could eventually extend beyond cancer testing and treatment.

"This is not just about cancer," Dr. Chaudhuri says. "It could provide insights into a wide range of diseases by helping us understand complex biological environments in the body."

Further studies are underway to validate the test in larger patient populations and move it into clinical use. Researchers are also exploring how different tumor microenvironment patterns may predict response to other therapies beyond immunotherapy.

"This work opens up an entirely new way of thinking about disease," Dr. Chaudhuri says. "We've essentially uncovered a world that was invisible to us before — and now we can access it with a simple blood test."

Aadel Chaudhuri, M.D., Ph.D., has patent filings related to liquid biopsy and cancer biomarkers, and has ownership interests in Droplet Biosciences and LiquidCell Dx. Aaron Newman, Ph.D., has patent filings related to digital cytometry, liquid biopsy and cancer biomarkers. He has served as a consultant to, and has ownership interests in, CiberMed and LiquidCell Dx.

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