Prostate cancer is the most common cancer in men in the United States and the second leading cause of cancer death in men. While the five-year survival rate after initial diagnosis is approximately 97% -- because most cases are caught while cancer is still confined to the prostate -- the picture changes dramatically once the cancer spreads. Metastatic prostate cancer carries a five-year survival rate of only about 31%, and is considered incurable with current therapies.
The most frequent sites of prostate cancer metastasis include the lymph nodes, liver, and bones. Bone metastasis is particularly debilitating, causing pain, fractures, and spinal cord compression. The reasons why prostate cancer cells preferentially travel to and flourish in certain organs are not fully understood, but the local cellular environment -- or tumor microenvironment (TME) -- is believed to play a decisive role.
The TME is a complex ecosystem surrounding a tumor that includes blood vessels, connective tissue (the extracellular matrix), signaling molecules called cytokines and chemokines, and importantly, various types of immune cells. Rather than simply recognizing and destroying cancer cells as they do with pathogens, many immune cells in the TME are actively co-opted by tumors to support their growth, invasion, and spread.
This review systematically examines how five key types of infiltrating immune cells -- macrophages, neutrophils, T cells, B cells, and mast cells -- interact with prostate cancer cells within the TME, and how these interactions drive or suppress metastasis. Understanding these mechanisms is essential for developing new immunotherapy strategies against metastatic prostate cancer.
Tumor-associated macrophages (TAMs) are the most abundant immune cells in the TME and are central orchestrators of prostate cancer metastasis. TAMs secrete the chemokines CCL5 and CCL2, both of which have been shown to dramatically enhance the migratory and invasive abilities of prostate cancer cells -- essentially acting as molecular guides that direct cancer cells toward blood vessels and distant organs, particularly bone.
CCL5 activates the STAT3 signaling pathway in prostate cancer cells, which drives epithelial-mesenchymal transition (EMT) -- a process in which cancer cells lose their epithelial identity and acquire a more mobile, invasive phenotype. CCL5 knockdown in mouse models blocked bone metastasis from prostate cancer, confirming its causal role. CCL2 similarly activates STAT3 and induces MMP9 upregulation, further enhancing ECM degradation needed for invasion.
TAMs also activate MMP9 (matrix metalloprotease 9), an enzyme that degrades the extracellular matrix and thus opens physical pathways for cancer cells to migrate through tissue. Androgen receptor (AR) knockout mice showed higher levels of both CCL2 and MMP9, suggesting that as prostate cancer progresses toward androgen independence, the pro-metastatic influence of TAMs increases.
Targeted depletion of TAMs in mouse models of bone metastasis reduced osteolysis (bone destruction) and tumor size in bone, while induction of macrophage apoptosis produced similar effects. These findings suggest that TAMs could be a viable therapeutic target -- not just in the primary prostate, but specifically at metastatic sites.
Tumor-associated neutrophils (TANs) have emerged as unexpected contributors to prostate cancer metastasis. Neutrophils are among the most prolific secretors of MMP9 in the TME -- producing more MMP9 in an immediate burst than macrophages secrete over an entire month. By degrading the ECM, these neutrophils help create the physical space necessary for cancer cells to invade and migrate.
However, the picture is more complex: some studies suggest neutrophils also attempt to limit cancer spread. Tissue samples from patients with bone-metastatic prostate cancer showed neutrophils forming neutrophil extracellular traps (NETs) -- web-like structures normally used to trap pathogens -- in close proximity to cancer cells, suggesting a defense-oriented response.
Mouse model experiments revealed a temporal shift: early in tumor progression, neutrophils appear to inhibit cancer cell growth through cytotoxic mechanisms. However, as the tumor matures, this cytotoxic ability diminishes, and the cancer cells effectively evade neutrophil-mediated killing. This progression from anti- to pro-tumor neutrophil behavior may represent an opportunity for therapeutic intervention at early stages of metastasis.
CD4+ T helper cells have been shown to actively promote prostate cancer metastasis. Cancer-secreted CXCL9 chemokine recruits CD4+ T cells to the tumor, where they downregulate the androgen receptor (AR) in prostate cancer cells. This reduced AR expression not only drives cancer cell invasion and migration but also feeds back to recruit more CD4+ T cells, creating a self-reinforcing pro-metastatic loop mediated by the FGF11-AR-MMP9 signaling axis.
CD4+ T cells also contribute to chemotherapy resistance. Studies show that CD4+ T cells in the tumor microenvironment secrete CCL5, which activates STAT3 in prostate cancer cells and renders them more resistant to docetaxel -- one of the main chemotherapy agents used for metastatic prostate cancer. This mechanism suggests that the immune microenvironment can directly undermine the effectiveness of standard treatments.
Regulatory T cells (Tregs) represent a particularly important immunosuppressive mechanism. Tregs are significantly enriched in bone metastases compared to localized prostate cancer, creating an immunosuppressive barrier that prevents cytotoxic T cells from destroying metastatic tumor cells. Treg recruitment to bone is mediated by the CXCL12-CXCR4 axis and CCL20-CCR6 signaling; blocking these signals reduces bone metastasis and increases the number of cytotoxic CD8+ T cells in the tumor region.
Tregs in bone metastasis additionally interact with dendritic cells expressing RANK, promoting their own expansion and altering bone metabolism -- suppressing osteoclast differentiation while enabling new bone formation around metastatic lesions. This metabolic manipulation further entrenches the cancer in the bone microenvironment.
Mast cells -- best known for their role in allergic reactions -- are infiltrating the prostate cancer TME and actively promoting tumor invasiveness. In the presence of mast cells, prostate cancer cells showed significantly increased invasive ability alongside reduced androgen receptor expression and upregulated MMP9 -- the same invasive machinery promoted by TAMs and TANs.
A key mechanism involves Protein Kinase D (PKD): prostate cancer cells expressing PKD2/3 secrete chemokines SCF, CCL5, and CCL11 that recruit mast cells to the tumor. In turn, mast cells activate PKD signaling in cancer cells, creating a bidirectional feedback loop that amplifies both mast cell infiltration and cancer cell invasiveness. Inhibiting PKD with the compound CRT0066101 reduced mast cell recruitment and blocked tumor progression in mouse models.
Mast cells infiltrating the tumor also express genes associated with tumor growth, metastasis, and immune escape, including ARG2, ANXA2, and TIMP1. The tumor suppressor gene SMAD4 is downregulated in tumor-associated mast cells, leading to ECM remodeling that favors cancer spread. Mast cells also promote resistance to both docetaxel chemotherapy and radiotherapy through the p38-p53-p21 signaling axis.
B cells remain the least understood immune cell type in the prostate cancer TME. They are more abundant in cancer regions than normal tissue, but conflicting studies report both favorable and unfavorable associations with patient outcomes. Their role may differ by patient demographics (higher B cell infiltration in Black males was associated with improved recurrence-free survival), suggesting the need for more research into B cell biology in prostate cancer.
The collective evidence reviewed here paints a picture of the prostate cancer TME as a profoundly complex, multi-cellular ecosystem that has been systematically co-opted to serve the tumor's metastatic agenda. Across macrophages, neutrophils, T cells, and mast cells, common themes emerge: elevated CCL5 and CCL2 cytokines driving invasion, upregulated MMP9 enabling ECM degradation, and suppressed cytotoxic CD8+ T cell function allowing cancer cells to escape immune destruction.
Metastatic prostate cancer is largely unresponsive to immune checkpoint inhibitors -- immunotherapies that have transformed outcomes in other cancers. This is because checkpoint inhibitors primarily work by reinvigorating cytotoxic T cells, but in metastatic prostate cancer the suppressive influences of Tregs, TAMs, and mast cells are too pervasive for T cell reactivation alone to overcome.
The therapeutic implication is clear: to effectively treat metastatic prostate cancer, strategies must target the TME itself -- either by blocking the pro-metastatic signals from infiltrating immune cells (for example, CCL5 or CXCL12 blockade), depleting or reprogramming TAMs and Tregs, or combining these approaches with existing therapies. Converting the immunosuppressive, pro-metastatic TME into one that supports anti-tumor immune activity represents one of the most promising frontiers in prostate cancer research.