Blood Proteins Before Surgery Reveal Which Prostate Cancers Will Return

A single blood draw taken before prostate cancer surgery may one day tell doctors which patients are most likely to see their disease return, according to a new study published in the journal Clinical Proteomics. Researchers in Norway analyzed immune-related proteins circulating in the serum of men about to undergo radical prostatectomy and discovered distinct immune signatures linked to biochemical recurrence and persistent prostate-specific antigen, or PSA, after surgery. The findings suggest that the state of a patient’s immune system before the tumor is even removed carries measurable information about the cancer’s future behavior, potentially opening the door to smarter, more personalized treatment planning.

The study, led by Indri Desiati and May-Britt Tessem of the Norwegian University of Science and Technology together with colleagues at Oslo University Hospital and St. Olavs Hospital, focused on 223 men drawn from two independent cohorts: 136 patients from Trondheim and 87 from Oslo. Each patient provided a serum sample before surgery, and the researchers measured the levels of proteins involved in inflammation and immuno-oncology using the Olink platform, a proximity extension assay technology capable of quantifying hundreds of proteins from tiny volumes of blood with high sensitivity and specificity. Thirty-four proteins overlapped between the inflammation and immuno-oncology panels and were analyzed across the combined cohort.

The clinical questions at the heart of the study are among the most consequential in prostate cancer management. Biochemical recurrence was defined as a PSA level of 0.2 nanograms per milliliter or higher following surgery, a signal that prostate tissue, or possibly residual or metastatic cancer cells, is once again producing the enzyme. PSA persistence, defined as a PSA level of 0.1 nanograms per milliliter or higher, indicates that PSA never fully fell after the operation, often hinting that cancerous tissue remained in the body. Both outcomes mark turning points at which patients and clinicians must decide whether additional treatment, such as radiotherapy or androgen deprivation therapy, is warranted.

Among the 34 immune proteins measured, one stood out with striking consistency. Interleukin 18, or IL18, a cytokine known to stimulate antitumor immune activity and promote the development of cytotoxic T lymphocytes and natural killer cells, was consistently lower in patients who later experienced recurrence or PSA persistence compared with those who remained disease-free. Reduced IL18 before surgery, the authors suggest, may reflect weakened antitumor immune surveillance already in place before the tumor was removed, leaving patients biologically vulnerable to regrowth.

The PSA persistence group told an even more distinctive immunological story. Patients whose PSA never dropped to undetectable levels showed lower levels of TNFSF12, also known as TWEAK, along with reduced CCL19, a chemokine that helps guide immune cells into lymphoid tissues, and lower CD244, a receptor involved in natural killer and T cell function. Perhaps most intriguingly, the researchers observed a broader trend toward reduced protein levels across the entire panel in the persistence group in both cohorts, a pattern consistent with what oncologists call an immune-desert profile, in which the tumor environment is largely devoid of active immune cell infiltration and activity.

To translate these observations into practical risk prediction, the team built protein-based classification models using partial least squares discriminant analysis with fivefold cross-validation and recursive feature elimination, then compared their performance against models built from standard clinical parameters including age, pre-surgical PSA, biopsy Gleason Grade Group, clinical tumor stage, and PI-RADS MRI scoring. The protein signatures outperformed the clinical models in both cohorts. In Trondheim, the protein model achieved an area under the receiver operating characteristic curve, or AUC, of 0.73 for recurrence compared with 0.64 for the clinical model, and 0.83 for PSA persistence compared with 0.81. In Oslo the gap was even wider: AUC values of 0.77 versus 0.54 for recurrence and 0.89 versus 0.63 for persistence.

When the researchers combined the immune protein data with clinical parameters, discrimination improved further still. The combined models reached an AUC of 0.75 for recurrence in Trondheim and 0.75 in Oslo, while for PSA persistence the combined models achieved AUC values of 0.91 in Trondheim and 0.88 in Oslo. These numbers, while requiring validation in larger independent cohorts, indicate that a simple pre-surgical blood test capturing immune signaling could meaningfully sharpen the risk picture that clinicians currently assemble from imaging, biopsy grading, and PSA measurements alone.

The technical rigor of the study strengthens confidence in its conclusions. Group comparisons were performed using one-way analysis of variance with false discovery rate correction to guard against spurious findings, and prognostic associations were evaluated with Cox proportional hazards models for recurrence and logistic regression for PSA persistence. Analyzing two geographically and administratively separate cohorts provided an internal replication of the key findings, particularly the consistent reduction of IL18 in patients destined for recurrence or persistence, and the immune-desert pattern in the persistence group.

Beyond its immediate predictive value, the study carries broader implications for the immunobiology of prostate cancer. Prostate cancer has traditionally been considered a relatively cold tumor, less responsive to the checkpoint inhibitor immunotherapies that have transformed the treatment of melanoma and lung cancer. The observation that specific, measurable immune states, one inflamed and one suppressed, are already detectable in peripheral blood before surgery suggests that systemic immune contexture plays a role in determining which tumors evade control. If confirmed, immune-proteomic profiling could help identify patients who might benefit from immunotherapeutic strategies or more aggressive adjuvant treatment, and could enrich clinical trials designed around immune biomarkers.

The authors emphasize that their findings support the potential of pre-surgical serum immune-proteomic profiling for risk stratification and treatment planning, pending further validation in larger independent cohorts. The work was funded by the Norwegian Cancer Society and the Central Norway Regional Health Authority, and the serum samples were provided through hospital biobanks with ethics approval and written informed consent from all participants. For the roughly 1.4 million men diagnosed with prostate cancer worldwide each year, the prospect of a routine blood test performed before surgery that reveals not only the tumor’s characteristics but the body’s immunological readiness to fight it represents a compelling step toward truly individualized cancer care. As proteomic technologies grow faster and cheaper, the immune fingerprint in a vial of blood may become as standard a part of the surgical workup as the MRI scan itself.

Subject of Research: Pre-surgical serum immune-proteomic biomarkers predicting recurrence after prostate cancer surgery

Article Title: Pre-surgical immune-proteomic profiles in serum identify inflamed and suppressed immune states associated with biochemical recurrence and PSA persistence in prostate cancer

Article References: Desiati, I., Bozorgpana, S., Ramberg, H., Berge, V., Tasken, K. A., Giskeødegård, G. F., Bathen, T. F., & Tessem, M.-B. (2026). Pre-surgical immune-proteomic profiles in serum identify inflamed and suppressed immune states associated with biochemical recurrence and PSA persistence in prostate cancer. Clinical Proteomics. https://doi.org/10.1186/s12014-026-09634-z

Image Credits: AI Generated

DOI: 10.1186/s12014-026-09634-z

Keywords: prostate cancer, biochemical recurrence, PSA persistence, immune biomarkers, serum proteomics, IL18, Olink, radical prostatectomy, risk stratification, immune-desert profile, TNFSF12, CCL19