A Simple Blood Protein Could Reveal How Aggressive Advanced Prostate Cancer Will Be

Prostate cancer remains one of the most common malignancies affecting men worldwide, and while many patients with localised disease are cured by surgery or radiotherapy, those whose tumours progress to a metastatic, treatment-resistant state face far grimmer prospects. One of the most pressing problems in the clinic is the lack of reliable, minimally invasive tools to predict how quickly the disease will advance once it reaches the stage known as metastatic castration-resistant prostate cancer, or mCRPC. A new study published in the British Journal of Cancer by a Danish research team led by Emma B. Hansen of Aarhus University Hospital now suggests that a protein floating freely in the bloodstream, shed by macrophages of the innate immune system, may fill precisely that gap. The findings point toward soluble CD163 as a candidate blood-based biomarker capable of flagging patients whose advanced disease is likely to progress rapidly on first-line therapy.

The study rests on a biological rationale that has been building for years. Macrophages, the scavenger cells of the immune system, are abundant infiltrators of prostate tumours, and their presence within the tumour microenvironment has repeatedly been linked to adverse outcomes. Tumour-associated macrophages are often polarised toward an immunosuppressive, so-called M2-like state that dampens anti-tumour immune responses, remodels tissue architecture, and promotes cancer cell invasion. Prior work from the same Aarhus group and collaborators showed that infiltrating regulatory T cells and macrophages act as adverse prognostic factors in prostate cancer, and other studies have tied M2 macrophage infiltration to extracapsular tumour extension and biochemical recurrence after radical prostatectomy. What has been missing is a way to read this immune activity without cutting into the tumour itself.

That is where soluble markers come in. CD163 is a receptor expressed on the surface of macrophages, best known as the scavenger receptor that clears complexes of haemoglobin and haptoglobin from the circulation. Crucially, CD163 exists naturally in a soluble form, sCD163, released from the macrophage surface, and it can be measured in serum with a standard enzyme-linked immunosorbent assay, a technique that has been available and refined since the early 2000s. The second marker examined in the study, soluble signal-regulatory protein alpha, or sSIRPα, is likewise shed from macrophages. SIRPα is a signalling regulator involved in macrophage activation, inhibiting inflammatory M1 responses while promoting M2 polarisation, and elevated expression of SIRPα-positive tumour-associated macrophages has been associated with poor outcomes and immune-evasive tumour contexts in other cancers, including oesophageal and bladder carcinoma.

To test whether these circulating markers carry clinical information in prostate cancer, the researchers measured serum sCD163 and sSIRPα in three patient cohorts representing different stages of the disease, totalling 646 patients. The design allowed them to compare marker levels between localised and metastatic disease and to ask whether the markers tracked with established measures of aggressiveness, such as tumour grade, within patients whose cancer was still hormone-sensitive. The results were nuanced. Both sCD163 and sSIRPα were significantly higher in patients with metastatic prostate cancer than in those with localised disease, confirming that systemic macrophage activity scales with tumour burden and dissemination. However, within the hormone-sensitive setting, neither marker correlated with clinical parameters of aggressiveness, suggesting that these proteins do not simply mirror how nasty an early-stage tumour looks under the microscope.

The most striking result emerged in the metastatic castration-resistant cohort. Among patients with mCRPC, those with high serum levels of sCD163 at the start of first-line treatment experienced significantly shorter progression-free survival, the standard measure of how long a therapy keeps the disease in check. Importantly, this association held up in multivariate analysis, meaning that sCD163 predicted outcome independently of the standard clinical parameters that clinicians already use, such as disease extent and other baseline characteristics. In the training cohort, the hazard ratio was 1.77, with a 95 percent confidence interval of 1.12 to 2.78 and a p-value of 0.014. In plain terms, patients with elevated sCD163 faced nearly a 77 percent higher risk of progression at any given time compared with those whose levels were lower.

What elevates this finding from an intriguing statistical association to a genuinely promising lead is that the researchers replicated it. In an independent validation cohort of 161 mCRPC patients, high sCD163 again predicted shorter progression-free survival on first-line treatment, with a hazard ratio of 1.85, a confidence interval of 1.15 to 2.97, and a p-value of 0.011. Replication in a separate group of patients is the gold standard for biomarker research, and it is a step that many candidate prognostic markers never achieve. The consistency of the effect size across the two cohorts lends credibility to the conclusion that sCD163 is not a statistical artefact but a real signal reflecting biology that matters for how advanced prostate cancer behaves under therapy.

The mechanistic interpretation is consistent with what is known about macrophages in late-stage cancer. As tumours metastasise and evolve resistance to androgen receptor blockade, the inflammatory and immunosuppressive milieu intensifies, and macrophages both infiltrate tumour tissue and become activated systemically. CD163 is upregulated on M2-polarised macrophages, and its soluble form is elevated in numerous inflammatory and malignant conditions, including melanoma, ovarian cancer, renal cell carcinoma, gastric cancer, colorectal cancer, sarcoma, and mantle cell lymphoma, where it has repeatedly shown prognostic value. The Danish findings now extend this pattern to mCRPC, positioning sCD163 as a circulating readout of the macrophage-driven immunosuppressive landscape that accompanies the most lethal phase of the disease. By contrast, sSIRPα, although elevated in metastatic disease, did not emerge as an independent prognostic factor, underscoring that the two markers, despite their shared cellular origin, are not interchangeable.

The clinical implications are worth spelling out. Men with mCRPC today face a sequence of life-prolonging but ultimately non-curative therapies, including androgen receptor pathway inhibitors such as abiraterone and enzalutamide, chemotherapy with docetaxel, and, for patients with specific molecular alterations, targeted agents and radioligand therapies. Choosing the right therapy at the right moment depends on prognostic information, and the tools currently available, from clinical risk models to inflammatory indices such as the neutrophil-to-lymphocyte ratio, are imperfect. A simple serum test for sCD163 could, if prospectively validated in interventional settings, help stratify patients at the start of treatment, identifying those with a high likelihood of early progression who might be candidates for more aggressive or alternative strategies, closer monitoring, or enrolment in clinical trials of novel combinations. Because the assay requires only a routine blood draw, it would be minimally invasive, relatively cheap, and easily repeatable over the course of treatment.

There are, of course, important caveats. sCD163 is not specific to prostate cancer; it rises in liver disease, infections, and other inflammatory states, so any clinical deployment would need to account for confounding conditions. The study measured the marker at baseline in retrospective cohorts, and while the validation design is strong, the ultimate test would be a prospective study demonstrating that incorporating sCD163 into treatment decisions actually improves patient outcomes. The authors also note that the data underlying the study are available from the corresponding author upon reasonable request under Danish data-sharing regulations, reflecting the patient-level nature of the analyses. The work was supported by the Novo Nordisk Foundation and the Danish Cancer Society, and the research was conducted under approvals from Danish regional ethics committees with appropriate consent or waiver procedures.

Nevertheless, the study adds a compelling piece to a rapidly growing picture in which the immune microenvironment of prostate cancer is no longer a black box but a measurable, quantifiable dimension of the disease. From single-cell transcriptomic dissections of immune-suppressive tumour niches to stromal gene expression signatures and circulating tumour DNA profiling, the field is converging on the idea that prognosis in advanced prostate cancer will increasingly be read from a combination of tumour-intrinsic and host-response signals. Soluble CD163, a protein first characterised as a haemoglobin scavenger more than two decades ago, now stands as one of the most practically accessible candidates on that list. For patients with metastatic castration-resistant prostate cancer, a single blood test that helps forecast the road ahead could mean earlier treatment switches, better-matched therapies, and, ultimately, more time. That possibility, grounded in two independent cohorts and a robust biological rationale, is precisely the kind of translational advance that turns basic immunology into bedside impact.

Subject of Research: Circulating macrophage markers as prognostic biomarkers in prostate cancer

Article Title: Clinical significance of circulating macrophage markers across different stages of prostate cancer: highlighting soluble CD163

Article References: Hansen, E. B., Antonsen, K. W., Jochumsen, M. R., Salachan, P. V., Bouchelouche, K., Hansen, T. F., Osther, P. J. S., Zedan, A. H., Borre, M., Møller, H. J., & Sørensen, K. D. (2026). Clinical significance of circulating macrophage markers across different stages of prostate cancer: highlighting soluble CD163. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03633-5

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03633-5

Keywords: prostate cancer, soluble CD163, sSIRPα, macrophages, biomarker, metastatic castration-resistant prostate cancer, progression-free survival, tumor microenvironment, ELISA, prognosis, immunosuppression, British Journal of Cancer