Plasma Proteins Help Predict Immunotherapy Success in Triple-Negative Breast Cancer
The new Plasma Immuno Prediction Score achieves 96% accuracy in forecasting TNBC outcomes, offering laboratories a powerful tool for precision oncology.
For laboratory professionals, the latest findings in plasma proteomics underscore how the clinical laboratory is becoming central to guiding cancer treatment decisions. The discovery of blood-based protein signatures that can predict immunotherapy outcomes in triple-negative breast cancer (TNBC) demonstrates how lab-developed tests and biomarker assays can directly influence patient care, moving precision oncology forward.
A news release explained that a team of researchers in China has identified a set of plasma proteins that can reliably predict whether patients with TNBC will respond to immunotherapy, potentially transforming treatment strategies for one of the most aggressive forms of breast cancer.
The study, published July 4, 2025, in Cancer Biology & Medicine, analyzed blood samples from 195 TNBC patients. Using high-sensitivity assays, scientists at Fudan University Shanghai Cancer Center and the Shanghai Institute for Biomedical and Pharmaceutical Technologies tracked 92 immune-related proteins before, during, and after immunotherapy.
They found that three proteins in particular—arginase 1 (ARG1), nitric oxide synthase 3 (NOS3), and CD28—were strongly linked to treatment outcomes. From this, the team developed a predictive model called the Plasma Immuno Prediction Score (PIPscore), which achieved nearly 86% accuracy in forecasting responses.
“This study transforms how we approach TNBC immunotherapy,” said Yizhou Jiang, MD, co-corresponding author. “By translating complex plasma proteomics into a practical score, we’ve bridged the gap between research and clinical utility.”
Breaking the Bottleneck in TNBC
Triple-negative breast cancer accounts for about 15% of breast cancer cases worldwide and is notoriously difficult to treat because it lacks the hormonal and HER2 targets used in other subtypes. Immunotherapy has emerged as a promising option, but predicting which patients will benefit remains a challenge.
Currently, clinicians rely on biomarkers like PD-L1 expression or tumor mutational burden. However, these markers often fail to capture the complexity of immune responses, leaving doctors without reliable tools to guide decisions. Tumor biopsies, another option, are invasive and impractical for frequent monitoring.
Yizhou Jiang, MD, Fudan University Shanghai Cancer Center, Fudan University, said “Plasma proteomics provides a non-invasive window into systemic immunity. Our work shows that the blood can tell us as much, if not more, than the tumor itself about how a patient will respond.”
How the Study Worked
The research team analyzed dynamic changes in plasma proteins over the course of immunotherapy. Patients who responded to treatment showed sharp rises in immune-activating proteins such as CXCL9 and interferon-gamma (IFN-γ). Those who achieved a pathologic complete response (pCR)—meaning no detectable cancer remained after treatment—had higher levels of ARG1 and CD28, but lower levels of NOS3.
According to the study, these proteins appear to regulate critical aspects of immune activation and tumor suppression. Elevated NOS3, for example, correlated with fewer CD8+ T cells in tumors, suggesting an immunosuppressive role. In contrast, ARG1’s role in arginine metabolism may boost T-cell function and strengthen immune attack on tumors.
To integrate these findings, the researchers developed the PIPscore, a composite of six proteins including ARG1, NOS3, and IL-18. This model stratified patients into high- and low-response groups with impressive precision. The area under the curve (AUC)—a common measure of predictive performance—was 0.858, indicating strong accuracy.
Perhaps most strikingly, the PIPscore predicted 12-month progression-free survival with 96% accuracy, highlighting its potential clinical value.
Linking Blood to Tumor Biology
To strengthen their conclusions, the team also used single-cell RNA sequencing to link blood protein signatures with changes in the tumor microenvironment. For example, patients with higher NOS3 levels showed reduced infiltration of CD8+ T cells into tumors, aligning blood-based findings with tissue-level biology.
“This dual approach—measuring proteins in the blood and validating them against the tumor microenvironment—offers a holistic view of how immunotherapy works,” Jiang said. “It underscores that systemic immunity, not just local tumor factors, dictates treatment success.”
Clinical Implications
The potential benefits of this approach are wide-ranging. Oncologists could use the PIPscore to determine upfront whether a TNBC patient is likely to respond to immunotherapy, sparing non-responders from ineffective treatments, unnecessary side effects, and high costs. Because the test is blood-based, it could be repeated over time, allowing clinicians to adjust treatment plans in real time.
“The PIPscore not only predicts response but also opens doors to targeting metabolic pathways like arginine deprivation to overcome resistance,” Jiang noted. “These findings underscore the importance of systemic immunity.”
Beyond TNBC, the researchers believe the method could be applied to other cancers where immunotherapy outcomes are highly variable.
In addition to plasma proteomics, the field of pharmacogenomics offers another layer of precision in cancer care by examining how genetic variations influence drug response.
When combined with tools like the PIPscore, pharmacogenomic profiling could help oncologists tailor both immunotherapy and supportive treatments to individual patients. For laboratory professionals, this integration underscores the expanding role of molecular diagnostics in personalizing therapy—ensuring patients not only receive the right drug but also the right dosage based on their genetic and immune profiles.
Next Steps
The study’s authors acknowledge that further validation is needed before the PIPscore can enter routine clinical practice. Larger, multi-center trials will be necessary to confirm its reliability across diverse patient populations. Still, experts view the findings as a major step toward more precise cancer care.
As immunotherapy adoption grows, laboratory professionals will be essential in validating, standardizing, and implementing predictive tools like the PIPscore in clinical practice. Their expertise in assay development, quality control, and biomarker interpretation ensures that discoveries at the research level can be reliably translated into real-world diagnostics, ultimately improving outcomes for patients with aggressive cancers like TNBC.
—Janette Wider
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