Advancing Precision Immunotherapy in Triple-Negative Breast Cancer Through Plasma Proteomics

Triple-negative breast cancer (TNBC) remains one of the most aggressive and difficult-to-treat subtypes of breast cancer due to the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) amplification. Although immunotherapy has emerged as a promising option for TNBC, responses are highly variable, and many patients experience either limited benefit or eventual disease progression. This has placed significant emphasis on the identification of predictive biomarkers to guide treatment decisions and improve outcomes for patients.

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Recent studies highlight the potential of plasma proteomics to change the way clinicians assess and optimize immunotherapy for TNBC. High-precision immune-related plasma proteomics profiling has demonstrated its ability to predict patient response to immunotherapy, offering a minimally invasive and scalable approach to biomarker testing.¹ Through the measurement of immune-regulation-related proteins in the blood, researchers have created the Plasma Immune Profiling score (PIPscore), which is a classification tool that can now allocate patients more accurately than relying only on tumor tissue–based methods.

"This study transforms how we approach TNBC immunotherapy," said Yizhou Jiang, PhD, co-corresponding author. "By translating complex plasma proteomics into a practical score, we've bridged the gap between research and clinical utility. The PIPscore not only predicts response but also opens doors to targeting metabolic pathways like arginine deprivation to overcome resistance. These findings underscore that systemic immunity, not just the tumor microenvironment, dictates treatment success."^1,2

Biomarkers that can effectively predict response to therapy in TNBC have been difficult to locate due to the heterogeneity of the disease. TNBC is fundamentally different from hormone receptor–positive or HER2-positive breast cancers, as it has no singled-out molecular driver, resulting in widely different treatment responses even among patient groups. Immunotherapy—checkpoint inhibitors in particular—has received a positive reaction in certain patient subgroups; however, it has been difficult to detect which ones will benefit most.³ Conventional biomarkers like PD-L1 expression have been inconsistent in efficacy prediction, reflecting the urgency for more reliable tools.

Plasma proteomics provides a fascinating option since it reflects the body’s overall immune response instead of focusing only on tumor-localized markers. Scientists can uncover the distinct patterns they are linked to the response or the resistance when they measure a large number of immune-related proteins concurrently. The PIPscore, for example, reflects not only tumor-intrinsic biology but also the patient’s overall immune fitness, providing a more holistic perspective on treatment potential.^1,2

The implications of these findings extend beyond patient stratification. By linking specific protein patterns to metabolic and immune pathways, researchers may also uncover new therapeutic targets. For example, the alteration of arginine metabolism has been detected as a possible cause of resistance to immunotherapy, implying that the combination of immunotherapy with metabolic interventions would result in increased therapeutic activity.¹ This method of combination could be the next great step in the management of TNBC, where biomarkers not only anticipate patient selection but also guide new therapeutic strategies.

Despite these advances, challenges still exist in the application of proteomics in routine clinical practice. Variability of the technology, the necessity for uniformity between different laboratories, and financial aspects are just some of the potential impediments. In addition, the capability of plasma-based biomarkers to predict will have to be confirmed by validation in large and diverse patient cohorts. As pointed out in an extensive review published in the Journal of Clinical Medicine, the issues of being reproducible and scalable still represent the main challenges for these biomarkers to be employed on a large scale.³

Plasma proteomics is developing as an effective tool to tailor treatment for triple-negative breast cancer (TNBC). Providing both predictive and mechanistic insights, tests like PIPscore can not only help distinguish the right immunotherapy use but also find the new combination strategies and, finally, make a positive impact on the patient’s prognosis when confronted with this severe form of cancer. With the ongoing clinical validation, immune profiling from blood samples will likely be incorporated into immune profiling in TNBC in the near future.

REFERENCES

1. Xiao Y, Zhang H, Xiao Y, et al. High-precision immune-related plasma proteomics profiling predicts response to immunotherapy in patients with triple-negative breast cancer. Cancer Biology and Medicine. Published online July 4, 2025:1-17. doi:j.issn.2095-3941.2025.0038

2. Blood test predicts immunotherapy efficacy in triple-negative breast cancer. EurekAlert! Published August 15, 2025. https://www.eurekalert.org/news-releases/1094877

3. Wang X, Collet L, Rediti M, et al. Predictive Biomarkers for Response to Immunotherapy in Triple Negative Breast Cancer: Promises and Challenges. Journal of Clinical Medicine. 2023;12(3):953. Doi:10.3390/jcm12030953