How prostate cancer turns immune cells into traitors - Futurity

Immunosuppressive cells present in the TME play active roles in immune exclusion and immunosuppression. ICB, immune checkpoint blockade; ECM, extracellular matrix; MDSCs, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages; CAFs, cancer-associated fibroblasts; MMPs, matrix metalloproteinases. Created with BioRender.com.

Breaking Down Immune Barriers: Revolutionary Discovery Reveals How Prostate Cancer Evades Treatment

Latest research identifies "traitor" immune cells and promising new strategies to outsmart them

The Discovery That Changes Everything

For years, prostate cancer patients and their doctors have wondered why immunotherapy—a treatment that has revolutionized care for melanoma, lung cancer, and other malignancies—has largely failed to deliver similar breakthroughs for prostate cancer. A groundbreaking study published in Molecular Cancer Research may finally provide the answer, along with a roadmap for overcoming this challenge.

Scientists led by Assistant Professor Shenglin Mei at Virginia Tech's Fralin Biomedical Research Institute have revealed how certain immune cells called macrophages are quietly helping prostate cancer grow by shielding tumors from attack and promoting metastasis. These cells, normally part of the immune system's housekeeping crew, are being reprogrammed by tumors to work against the body's natural defenses.

The Cellular Double Agents

Among four macrophage subtypes identified, one stood out: a group marked by the proteins SPP1 and TREM2. These cells were found clustered inside tumor regions—not in surrounding tissue—and were linked to blood vessel growth, impaired immune activity, and the spread of cancer in the body.

What makes this discovery particularly significant is the precision with which the researchers mapped these cellular interactions. Using spatial analysis—a technique that maps where cells are located within a tumor—researchers found that inflammatory, potentially tumor-fighting macrophages tended to remain outside tumor boundaries, but a specific subtype that produces the troublesome SPP1 and TREM2 proteins was found deep inside the tumors, in close contact with cancer cells.

Dr. Mei explains the significance: "Macrophages often aid in fighting cancers. However, certain subtypes foster an immune-suppressive environment, hindering the body's natural defenses."

A Path Forward: Blocking the Blockers

The most encouraging aspect of this research comes from the experimental validation. In mice with prostate tumors, researchers used an antibody to block the SPP1 protein and found that tumors were more vulnerable to immunotherapy. While immune checkpoint inhibitors have worked in many other cancers, they've failed in prostate cancer. But in this study, combining anti-SPP1 treatment with immunotherapy significantly boosted the immune response.

"Targeting SPP1/TREM2 tumor associated macrophages reversed immunosuppression, allowing more T cells—the immune system's primary defenders—to infiltrate the tumor, resulting in slowed cancer progression," Mei says.

The Broader Immunotherapy Revolution

This discovery comes at a time when the field of prostate cancer immunotherapy is experiencing unprecedented momentum. A recent clinical trial involving an experimental drug called AMG 509/Xaluritamig saw a reduction in blood levels of prostate-specific antigen (PSA), a tumor marker, in nearly half of participating patients. This drug represents a new class called T cell bi-specifics, which force tumor cells and immune cells together.

Nanoparticle Breakthrough

Researchers from the University of Sheffield have found a new form of immunotherapy using innovative nanoparticles that can delay resistance to hormone therapy and help men with prostate cancer live longer. The study shows using nanoparticles to activate immune cells to kill cancer cells delays resistance to powerful first-line treatment.

The Sheffield team discovered that a type of white blood cell called a macrophage collects in large numbers around tumour blood vessels during hormone therapy treatment—making them well-placed targets for immunotherapy. Their nanoparticles act like targeted missiles, delivering immunotherapy drugs specifically to these immune cells.

CAR-T Cell Advances

Researchers at City of Hope Hospital in Duarte, California, are reporting promising results with CAR-T cell therapy, which involves engineering immune cells called T cells after they've been obtained from a patient's own body. The engineered cells are studded with proteins called chimeric antigen receptors (CARs) that bind to specific molecular targets on cancer cells.

Understanding the Challenge

Prostate cancer is traditionally considered as an immunologically "cold" tumor with low tumor mutation burden, low expression of PD-L1, sparse T-cell infiltration, and a immunosuppressive tumor microenvironment. This explains why standard immunotherapies have struggled to gain traction.

However, recent research suggests this may not be the full story. TREM2 expression levels vary significantly among different tumor cells, and it can regulate tumor progression by modulating various signaling pathways. Understanding these mechanisms is opening new therapeutic avenues.

The Clinical Pipeline

The U.S. Food and Drug Administration (FDA) has approved three immunotherapy treatments for prostate cancer: one cancer vaccine and two checkpoint inhibitors. Meanwhile, almost 200 TAM-reprogramming agents are being investigated in more than 700 clinical trials, highlighting the intense research focus on manipulating tumor-associated macrophages.

Current FDA-approved immunotherapies for prostate cancer include:

  • Sipuleucel-T (Provenge): The first FDA-approved immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer
  • Pembrolizumab (Keytruda): For tumors with specific genetic markers (MSI-H/dMMR)
  • Dostarlimab: For similar genetic signatures

What This Means for Patients

This research represents more than just scientific progress—it offers hope for the future of prostate cancer treatment. By identifying the specific mechanisms that allow prostate cancer to evade immune attack, researchers are developing targeted strategies to overcome these barriers.

For patients currently battling prostate cancer, several takeaways emerge:

  1. Clinical Trial Opportunities: The rapid pace of immunotherapy development means new trials are continuously opening. Patients should discuss clinical trial options with their oncologists.
  2. Combination Approaches: The most promising strategies involve combining different immunotherapy approaches or pairing immunotherapy with existing treatments like hormone therapy.
  3. Personalized Medicine: Understanding individual tumor characteristics, including immune cell patterns, may help predict which patients will benefit from specific immunotherapy approaches.

Looking Ahead

As one researcher noted, "this is a really exciting time to be studying immunotherapy" for prostate cancer. The convergence of advanced technologies like single-cell RNA sequencing, spatial transcriptomics, and targeted drug delivery is accelerating discoveries that could transform treatment.

The Virginia Tech discovery about SPP1/TREM2 macrophages provides a clear target for drug development, while the nanoparticle and CAR-T approaches offer complementary strategies for overcoming immune resistance.

For the prostate cancer community, these developments signal that the immunotherapy revolution that has transformed other cancers may finally be arriving for prostate cancer—bringing with it the potential for longer survival and even cures for patients facing this challenging disease.

Sources and Further Reading

  1. Pastor, J. (2025). "How prostate cancer turns immune cells into traitors." Futurity. Virginia Tech. https://www.futurity.org/prostate-cancer-macrophages-3286842-2/
  2. Siddiqui, B. (2024, May 10). "What's new in immunotherapy for prostate cancer?" MD Anderson Cancer Center. https://www.mdanderson.org/cancerwise/what-s-new-in-immunotherapy-for-prostate-cancer-treatment.h00-159697545.html
  3. University of Sheffield. (2024, August 15). "New hope for prostate cancer: new form of immunotherapy could prevent resistance to hormone therapy." https://sheffield.ac.uk/news/new-hope-prostate-cancer-new-form-immunotherapy-could-prevent-resistance-hormone-therapy
  4. Prostate Cancer UK. (2024). "Could nanoparticles finally unlock the potential of immunotherapy for prostate cancer?" https://prostatecanceruk.org/about-us/news-and-views/2024/08/nanoparticle-immunotherapy-for-prostate-cancer
  5. Cancer Research Institute. (2024, September 6). "Prostate Cancer Awareness Month: Unlocking the Power of Immunotherapy to Combat a Common Men's Cancer." https://www.cancerresearch.org/blog/september-2024/prostate-cancer-awareness-month-unlocking-the-power-of-immunotherapy-to-combat-a-common-mens-cancer
  6. Harvard Health. (2024, September 16). "CAR-T immunotherapy for prostate cancer?" https://www.health.harvard.edu/blog/car-t-immunotherapy-for-prostate-cancer-202409163070
  7. Lei, X., et al. (2024). "Mechanisms of TREM2 mediated immunosuppression and regulation of cancer progression." Frontiers in Oncology, 14. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1375729/full
  8. Che, J., et al. (2025). "The application of emerging immunotherapy in the treatment of prostate cancer: progress, dilemma and promise." Frontiers in Immunology, 16. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1544882/full

For the most current information on clinical trials, visit ClinicalTrials.gov or discuss options with your oncology team.

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How prostate cancer turns immune cells into traitors - Futurity

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