Rogue Immune Cells Help Prostate Cancer Spread—and How Scientists Are Fighting Back

Scientists have identified immune cells that betray the body by helping prostate cancer spread and resist treatment—and discovered how to turn them back into cancer fighters.

The study reveals how certain macrophages, normally the immune system’s cleanup crew, become corrupted accomplices that shield tumors from attack and fuel deadly bone metastases.

Published as the cover story in Molecular Cancer Research, the research pinpoints a specific subset of tumor-associated macrophages marked by SPP1 and TREM2 proteins that cluster deep inside prostate tumors. Unlike their cancer-fighting cousins that remain outside tumor boundaries, these corrupted cells actively suppress immune responses and promote cancer spread.

The Body’s Janitors Turn Rogue

Macrophages typically serve as the immune system’s housekeeping crew, engulfing dead cells and responding to infections. But in prostate cancer, some undergo a sinister transformation. “Macrophages often aid in fighting cancers,” explains Assistant Professor Shenglin Mei of Virginia Tech’s Fralin Biomedical Research Institute, who led the study. “However, certain subtypes foster an immune-suppressive environment, hindering the body’s natural defenses.”

Using spatial analysis—a technique that maps cell locations within tumors—researchers discovered four distinct macrophage subtypes. One stood out as particularly troublesome: cells producing SPP1 and TREM2 proteins were found embedded within tumor regions, closely mingling with cancer cells rather than fighting them.

Key Findings That Could Change Treatment

The international team’s discoveries include several game-changing insights:

• SPP1+/TREM2+ macrophages were significantly enriched in metastatic tumors compared to primary cancers
• Higher levels of these corrupted cells correlated with shorter progression-free survival in patients
• Blocking SPP1 protein restored immune function and made tumors vulnerable to immunotherapy
• Combined anti-SPP1 and immunotherapy treatment significantly slowed cancer progression in mouse models

These findings could explain why immune checkpoint inhibitors—successful against many other cancers—have failed in prostate cancer treatment.

From Discovery to Potential Treatment

The research team tested their theory using mouse models of prostate cancer. When they blocked the SPP1 protein with antibodies, something remarkable happened: tumors became more susceptible to immunotherapy. The treatment allowed more T cells—the immune system’s primary defenders—to infiltrate and attack the cancer.

“Targeting SPP1/TREM2 tumor associated macrophages reversed immunosuppression, allowing more T cells to infiltrate the tumor, resulting in slowed cancer progression,” Mei noted.

This discovery carries urgent implications. Prostate cancer ranks as the second most commonly diagnosed cancer in men globally, with an estimated 1.47 million new cases worldwide in 2022. The disease becomes particularly lethal when it spreads to bones, where current treatments often fail.

Advanced Technology Reveals Hidden Players

Mei’s team combined cutting-edge techniques including single-cell RNA sequencing, spatial transcriptomics, and NanoString digital spatial profiling to map immune cell activity with unprecedented precision. They analyzed datasets from hundreds of prostate cancer patients, ensuring their findings held across human samples, mouse models, and disease stages.

The spatial analysis revealed a stark pattern: inflammatory macrophages that could fight cancer remained relegated to areas outside tumors, while the SPP1+/TREM2+ cells had privileged access to tumor cores where they could do maximum damage.

This multi-institutional collaboration involved researchers from Virginia Tech, Harvard Medical School, Massachusetts General Hospital, the University of Chicago, and Sweden’s Karolinska Institute. The project received support from the Prostate Cancer Foundation and National Institutes of Health.

As researchers move toward clinical trials, this discovery offers hope for the thousands of men facing advanced prostate cancer. By unmasking these cellular traitors and learning to reprogram them, scientists may finally crack the code on why prostate cancer has proven so resistant to modern immunotherapy.