Unraveling the microbial landscape in prostate cancer: pathogenesis to therapy

Abstract

Emerging evidence suggests a role of microbiota in prostate cancer, yet this association remains poorly understood. This review systematically examines microbes from the skin, oral cavity, gut, urinary tract, and the prostate cancer microenvironment, summarizing how these communities affect prostate cancer initiation, progression, and therapeutic response. We highlight key molecular pathways and metabolic reprogramming events underlying host-microbiota interactions and outline current findings and knowledge gaps to guide microorganism-based therapeutic strategies.

Introduction

Prostate cancer (PCa) is the second most common malignancy among men worldwide and its mortality rate is projected to more than double over the next decade¹. Early-stage localized prostate cancer is associated with favorable survival and prognosis when treated with antiandrogen therapies. However, prolonged use of these therapies often leads to the progression of PCa into castration-resistant prostate cancer (CRPC), a treatment-resistant state that is more prone to metastasis^2–4. Metastatic castration-resistant prostate cancer (mCRPC) is the advanced stage of PCa, and recurrence and therapeutic resistance remain significant challenges for the management of mCRPC^5,6.

The microbiome is composed of bacteria, fungi, archaea and viruses that live in symbiosis with their hosts. A growing body of evidence indicates that dysregulated microbiome can modulate tumor initiation and progression^7,8. With the rapid development of DNA and RNA sequencing technologies, the microbiome in host has been well discovered^9,10. By implementing gold-standard contamination control measures and addressing the challenge of low microbial abundance, research on tumor-associated microbiomes has progressed from descriptive analyses to in-depth investigations of causal relationships and underlying molecular mechanisms^11–13. Emerging evidence suggests that the microbiome affects tumor progression mainly through dysfunction of drug metabolism, dysregulation of tumor-associated signaling pathways, resetting of epigenetic modifications, induction of chronic inflammation, and reprograming of microenvironment^7,14–18. These findings highlight the critical role of the microbiome as an external factor in tumor biology, complementing intrinsic tumor characteristics.

However, due to its anatomical location, the prostate lacks the rich commensal microbiome found in the gastrointestinal tract, leading to a limited understanding of microbial signatures associated with PCa^19,20. Whether and how the microbiome affects PCa progression remain under-investigated²¹. A deeper understanding of the specific features and mechanistic roles of the microbiome in PCa is essential for advancing personalized and precision oncology²². Here, we will provide a comprehensive overview of the challenges in investigating the role of the microbiota in PCa, highlighting how microbiota from different organs can modulate disease progression and the strategies they employ in regulating tumor development. This in-depth analysis aims to establish a foundational microbial framework to inform both monotherapy and combination strategies targeting the PCa microbiome.

Challenges in investigating the role of the microbiota in prostate cancer

Analyses of extensive publicly available whole-genome and whole-transcriptome sequencing datasets have identified a variety of tumor-associated microbiomes, laying the groundwork for the initial characterization of microbial communities^23–25. However, despite the use of various contamination control strategies, efforts to identify cancer-resident microbiota through analyses of whole-genome and whole-transcriptome sequencing data from The Cancer Genome Atlas (TCGA) and other public repositories remain hindered by sample contamination and imprecise sequence alignment^26,27. For instance, a representative publication in this field by Dr. Rob Knight’s lab was retracted after concerns were raised about the robustness of specific microbial signatures reported to be associated with cancer. Critical flaws in the computational methods were uncovered, in which human DNA reads were mistakenly classified as bacterial. These errors undermined the validity of the reported tumor-associated microbial signatures and ultimately led to the withdrawal of the study²⁸.

Currently, 16S rRNA gene sequencing and metagenomic sequencing remain the principal methodologies for characterizing tumor-associated microbiome²⁹. Compared with other tissues or organs that are frequently exposed to microorganisms (i.e., colorectal cancer, gastric cancer, lung cancer, cervical cancer, and skin cancer), PCa harbors relatively few resident microbiomes. Traditionally, the urinary system has been considered a sterile environment. On the one hand, this view suggests the fact that microbial presence in the urinary tract is minimal, and on the other hand, it implies that the urinary system may possess a strong immune response capable of clearing exogenous microorganisms. Nevertheless, the minimal presence of microbiota poses a challenge for identifying resident microbes in PCa. Moreover, the samples used for sequencing in PCa studies are typically biopsy specimens. The low biomass of prostate samples and substantial cohort heterogeneity contribute to highly variable and sometimes conflicting microbial profiling results^30–32. Therefore, most studies investigating the association between PCa and microbiota focus on microbes originating from other organs, which influence PCa progression through endocrine pathways. We will further discuss this point in the following sections.

At present, most studies exploring the association between microbiota and PCa progression remain largely descriptive. Limitations in available animal models hinder the ability to validate the causal role of microbiota in the initiation and progression of PCa, making it difficult to establish a definitive link between microbiota and PCa development. Furthermore, our understanding of the molecular mechanisms by which microbiota directly interact with PCa cells or modulate the tumor microenvironment remains limited. Further investigation into these mechanisms holds promise for the development of targeted therapies against PCa.

Microbiota from different organs modulate prostate cancer progression

Several studies have shown that PCa can be influenced by microbiota originating from distant organs. This indirect regulation may occur through mechanisms such as the induction of systemic inflammation, modulation of host metabolism, and alternative pathways of androgen synthesis^33–36. Herein, we will summarize whether and how microbes originating from different tissues or organs modulate PCa progression (Fig. 1 and Table 1).

Fig. 1. Microbiota derived from different organs are associated with prostate cancer risk.

Red indicates association with increased prostate cancer risk, blue indicates association with decreased risk. The microbiota shown has been repeatedly reported across multiple studies to be associated with an increased or decreased risk of prostate cancer.

Table 1.

Summary of microbiome studies in prostate cancer

Source	Risk	Main microbiome profiles	Refs
Skins	Increased PCa risk	Neisseria	42
		Propionibacterium acnes	43
Oral cavity	Increased PCa risk	Catonella, Oribacterium, Pauljensenia, Campylobacter A and Lachnoanaerobaculum	63
Oral cavity	Decreased PCa risk	Gemella, Streptococcus, Solobacterium and Aggregatibacter	63
Gut	Increased PCa risk	Bacteroides, Escherichia, Proteobacteria and Lachnospiraceae	77
		Bacteroides	78
		Bacteroides	80
		Verrucomicrobiae, Verrucomicrobiaceae, Verrucomicrobiales, Akkermansia and Butyrivibrio	84
		Allisonella, Oscillibacter, Eubacterium and Senegalimassilia	85
		Victivallis, Akkermansia, Odoribacter and Butyrivibrio	86
		Ruminococcaceae	87
		Marvinbryantia, Romboutsia, Ruminococcaceae and Sutterella	88
Gut	Decreased PCa risk	Selenomonadales	77
		Faecalibacterium	78
		Mollicutes and Tenericutes	84
		Eubacterium	86
		Anaerotruncus, Eisenbergiella, Olsenella and Parabacteroides	88
		Alphaproteobacteria and Ruminococcaceae	89
Urethra	Increased PCa risk	Faecalibacterium, Staphylococcus, Ruminococcaceae, Neisseria and Agathobacter	115
		Streptococcus, Prevotella, Peptoniphilus, Negativicoccus, Actinomyces, Propionimicrobium, and Facklamia	117
		Ochrobactrum, Sphingomonas and Propionicimonas	118
		Escherichia	122
		Propionimicrobium	123
Urethra	Decreased PCa risk	Methylobacterium/Methylorubrum, Faecalibacterium and Blautia	117
		Eubacterium and Defluviicoccus	118
Prostate	Increased PCa risk	Prevotella, Cupriavidus and Propionibacterium	127
		Staphylococcus	128
		Helicobacter	129
		Escherichia, Propionibacterium and Pseudomonas	130
		Shewanella	131
		Escherichia and Propionibacterium	134
		Staphylococcus	136
		Propionibacterium	32,137,138,140–143,145,147–149
		Propionibacterium and Staphylococcus	144
		Mycoplasma	157
Prostate	Decreased PCa risk	Cupriavidus and Methylobacterium	127
		Lactobacillus	128
		Staphylococcus and Vibrio	131
		Listeria, Methylobacterium and Xanthomonas	135
		Streptococcus and Mannheimia	136
		Streptococcus	144

PCa, prostate cancer.

Cutaneous microbiota and prostate cancer

As the largest organ in the human body, the skin harbors a rich and complex microbiome^37,38, the composition and diversity of which are influenced by a variety of factors, including host age, ethnicity, geographic location, lifestyle, immune status and disease state³⁹. Dysbiosis of the cutaneous microbiome has been implicated in various dermatological and systemic diseases⁴⁰. Considering the anatomical distance between the skin and the prostate, there is a lack of conclusive evidence for an association between its microbiome and PCa⁴¹. However, a few studies have reported a potential association. A Mendelian randomization (MR) study suggested a significant association between the presence of Neisseria on dry skin and the risk of PCa⁴². In addition, Propionibacterium acnes (also known as Cutibacterium acnes) has been detected in both the urinary tract and skin of patients with PCa, suggesting that poor hygiene practices or certain sexual behaviors may facilitate translocation of cutaneous microbiome into the genitourinary tract⁴³.

Oral microbiota and prostate cancer

The oral cavity directly contacts with various foods and environmental exposures during alimentation, creating favorable conditions for microbial infection and colonization⁴⁴. The surfaces of teeth further support the development of a highly complex commensal microbiota. Consequently, dysbiosis of the oral microbiota can lead to a range of oral diseases, including gingivitis, periodontitis, dental caries, and even oral carcinoma⁴⁵. As the gateway to the digestive tract, the mouth is contiguous with the gastrointestinal system, and a subset of gut microbes originates from the oral niche⁴⁶. More importantly, oral microbe can translocate to distant organs via the bloodstream, inducing chronic inflammation that may promote tumorigenesis^47,48. Studies indicate that oral infectious diseases can trigger systemic inflammation, as indicated by increased levels of C-reactive protein and pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6, which may subsequently contribute to the development of prostatitis⁴⁹. Indeed, individuals with prostatitis have a significantly increased risk of developing PCa^50–52. Furthermore, periodontitis has been associated with elevated prostate specific antigen (PSA) levels⁵³ and patients with moderate to severe prostatitis accompanied by periodontitis present significant higher PSA levels⁵⁴. Accordingly, periodontal therapy may not only restore oral health but also help alleviate prostate-related diseases and reduce serum PSA levels⁵⁵.

Several investigations underscore significant associations between the oral microbiome and PCa risk^56–58. Dysbiosis and microbial replacement of oral microbiome have been associated with the risk of PCa^59,60. Recent studies have shown that DNA of the periodontitis pathogens Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola and Escherichia coli has been detected in prostate secretions of men with concurrent periodontitis and prostate diseases⁶¹. In contrast, another study found no significant differences in most periodontal pathogens compared to controls when using real-time polymerase chain reaction (PCR) to analyze radical prostatectomy specimens from patients. Only Fusobacterium nucleatum exhibited higher expression in benign prostatic hyperplasia (BPH), inflamed and cancerous regions, although its abundance did not differ significantly among these sites⁶². A MR study identified 27 and 42 bacterial species from tongue dorsum and saliva samples, respectively, that were significantly associated with PCa risk. Specifically, Oribacterium, Pauljensenia, Campylobacter A, Catonella, Lachnoanaerobaculum, and the unclassified taxon RUG343 were linked to an increased risk of PCa, while Aggregatibacter, Solobacterium, Streptococcus, and Gemella were associated with a reduced risk⁶³. However, other studies have reached different conclusions. A MR analysis found no causal relationship between periodontitis and prostate disease, citing insufficient evidence for a direct link⁶⁴. Likewise, a prospective study of chronic periodontitis patients without prior prostate pathology demonstrated that periodontal intervention did not affect PSA levels⁶⁵. A retrospective study revealed no significant differences in the alpha diversity or beta diversity of the oral microbiota between PCa patients and healthy controls⁶⁶. Collectively, the association between oral microorganisms and PCa risk remain controversial. Further studies are required to establish a causal relationship between oral microorganisms and PCa development.

Gut microbiota and prostate cancer

The gut microorganisms play a pivotal role in regulating a variety of physiological functions, including the development of the immune system and the synthesis of specific nutrients^67,68. Disruption of the homeostasis between the gut microbiota and its host results in dysbiosis, characterized by shifts in microbial community composition, aberrant metabolic outputs and altered secretion of extracellular vesicles. These perturbations not only compromise intestinal health but are also closely associated with a range of pathophysiological conditions, including cancer^69–73. Although findings have been inconsistent and certain associations between specific microorganisms and PCa risk remain contradictory, a substantial body of evidence nonetheless indicates that the gut microbiota is closely associated with the initiation and progression of PCa^74–76.

The studies of gut-prostate axis have demonstrated the role of gut microorganisms in PCa. First, the abundance of several gut microorganisms has been repeatedly investigated in PCa patients. A systematic reviews and meta-analysis have demonstrated that PCa patients exhibit a significantly reduced gut microbiota alpha diversity, with elevated abundances of Bacteroides, Proteobacteria, Bacteroidia, Clostridia, Bacteroidales, Clostridiales, Prevotellaceae, Lachnospiraceae, Prevotella, Escherichia and Faecalibacterium, whereas Actinobacteria, Bacteroidetes, Firmicutes, Selenomonadales, Veillonella and Megasphaera are comparatively depleted⁷⁷. Another study also showed a significant increase in the relative abundance of Bacteroides massiliensis and a significant decrease in Faecalibacterium prausnitzii and Eubacterium in PCa patients⁷⁸. Obesity is considered to be an important factor affecting gut microbiome. A study of overweight and obese PCa patients paired with healthy controls showed that there was no significant difference in alpha diversity between the two groups, but there was a significant difference in beta diversity, suggesting specific changes in the gut microbiome of PCa patients⁷⁹. In contrast, another investigation using 16S rRNA sequencing of gut samples from PCa patients found that overall microbial features could not distinguish patients from controls, with only Bacteroides exhibiting increased abundance in the cancer group⁸⁰. Additional studies have also reported minimal overall differences in gut microbiome between PCa patients and healthy controls^80–82. For instance, putative pro-inflammatory genera such as Bacteroides and Streptococcus were slightly enriched in PCa, but the differences were not statistically significant⁸³.

Second, multiple MR studies have revealed that the alterations of specific gut microorganisms are closely associated with the occurrence of PCa. For instance, the increased abundance in some specific gut microorganisms, such as Verrucomicrobiae, Verrucomicrobiaceae, Verrucomicrobiales, Akkermansia and Butyrivibrio, have been observed in PCa patients and are closely associated with an increased risk of PCa⁸⁴. In other studies, microorganisms such as Victivallis, Odoribacter, Enterobacteriaceae, Enterobacteriales, Gordonibacter, Gordonibacter pamelaeae, Bacilli, Lactobacillales, Marvinbryantia, Romboutsia, Ruminococcaceae UCG002, Sutterella, Ruminococcus, Oscillibacter, Barnesiella and Butyricicoccus have similar trends^85–88. In contrast, some other gut microorganisms may confer protective effects against PCa. MR analyses have shown that the prevalence of Mollicutes and Tenericutes is significantly reduced in PCa patients and these microorganisms are associated with a decreased risk of PCa⁸⁴. In addition, higher abundances of Eubacterium ruminantium, Candidatus Soleaferrea, Ruminococcaceae UCG003, Peptostreptococcaceae, Verrucomicrobia, Rikenellaceae, Anaerotruncus, Eisenbergiella, Olsenella, Parabacteroides and Alphaproteobacteria have been shown to be associated with a reduced risk of PCa^86–89.

Third, gut microbial dysbiosis is often associated with a pro-inflammatory state in the prostate, which may contribute to the development and progression of PCa. In patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), the gut microbiome is altered, with significant increases in the abundances of Bacteroides, Romboutsia, Escherichia–Shigella, Ruminococcus, Enterobacter, Pseudomonas, Clostridium sensu stricto 1 and Lachnoclostridium, while Blautia, Faecalibacterium, Bifidobacterium, Prevotella 9, Alistipes and Dialister are relatively depleted. These changes are accompanied by enrichment of pathways related to development and regeneration⁹⁰. Several MR studies have further identified positive associations between increased prostatitis risk and the Faecalibacterium, Lachnospiraceae UCG-004, Sutterella, Gastranaerophilales, Holdemania and the Actinomycetales, whereas Methanobacteria, Methanobacteriaceae, Erysipelatoclostridium, Parasutterella, Slackia and Verrucomicrobia show inverse correlation with prostatitis risk^91–93. Additional lines of evidence also suggest a link between gut microbiota and PCa progression. For instance, in preclinical models, gastrointestinal colonization by Helicobacter pylori under conditions of wnt signaling dysregulation promotes prostate carcinogenesis by systemic inflammation⁹⁴. The gut microbiome of rats with chronic non-bacterial prostatitis (CNP) was significantly altered with a significant increase in the abundance of Pseudomonas and Eubacterium⁹⁵.

Specific to PCa, gut microbiota also influences the efficacy of androgen deprivation therapy (ADT). As revealed by 16S rRNA sequencing, the gut microbiome of patients with hormone-sensitive PCa and CRPC have different changes undergoing ADT. In CRPC patients, the abundance of Phascolarctobacterium and Ruminococcus is markedly increased, accompanied by significant activation of terpenoid/polyketide metabolism and ether lipid metabolism pathways⁹⁶. In PCa patients, ADT induces reprogramming of gut microbiota. ADT leads to the enrichment of Ruminococcus gnavus and Bacteroides and the reduction of Lachnospira and Roseburia. The Firmicutes/Bacteroidetes ratio is decreased, with notable enrichment of gene pathways associated with lipopolysaccharide (LPS) biosynthesis, propanoate metabolism and energy cycling⁹⁷. Antiandrogen therapies (i.e., bicalutamide, enzalutamide and abiraterone acetate) promote the enrichment of specific gut microorganisms such as Akkermansia muciniphila, Ruminococcaceae and Lachnospiraceae. These alterations are accompanied by upregulation of microbial gene pathways involved in steroid biosynthesis and steroid hormone metabolism, as well as enhanced activity in pathways related to caffeine metabolism and glycosaminoglycan degradation⁹⁸. Interestingly, the combination of antiandrogen therapy and chemotherapy further alters the composition of the gut microbiota in PCa patients, resulting in an enrichment of bacteria such as Enterobacter, Klebsiella, Vibrionales and Vibrionaceae⁹⁹. Emerging evidence has indicated a crucial role of gut microorganisms in regulating androgen signaling in PCa, we will further discuss these mechanisms in the following sections.

Gut microbiota also plays a regulatory role in the therapeutic resistance and metastasis, the advanced features of PCa progression. Compared with hormone-sensitive PCa, CRPC exhibits increased abundances of Gemella and Lactobacillus¹⁰⁰. In animal models, Ruminococcus is significantly enriched in the gut microbiota of CRPC Fecal microbiota transplantation (FMT) from these castration-resistant donors enhances LPCAT1 expression and activates DNA repair pathways, thereby accelerating PCa progression in recipient mice¹⁰¹. More exciting, gut commensal bacteria serve as an alternative source of androgens by converting androgen precursors into their active forms. This process contributes to the expansion of these bacteria during ADT and promotes the development of CRPC. FMT from CRPC mice and patients rendered the recipient mice resistant to ADT, whereas administration of FMT from hormone-sensitive PCa patients or Prevotella stercorea effectively inhibit tumor growth¹⁰². The gut microbiome may regulate PCa metastasis. Metastatic prostate tumors harbor higher abundances of Ruminococcaceae and lower levels of Prevotella, whereas primary prostate tumors are enriched with Lachnospiraceae. Additionally, the androgen degradation pathway is significantly upregulated in metastatic cases¹⁰³. Whether and how the gut microbiota regulates PCa metastasis remains largely under-investigated.

Urinary microbiota and prostate cancer

It was long believed that urine was sterile; however, recent studies have revealed the presence of microbial communities within the genitourinary system^104–106. Given the anatomical proximity of the urethra to the prostate, urinary microbes may translocate into and colonize the prostate, potentially triggering inflammation that facilitates carcinogenesis^107–110. Furthermore, the observed associations between urinary microbiota and PCa risk suggest that urinary microbial signatures may have clinical potential for early diagnosis of PCa¹¹¹.

Microorganisms including Escherichia coli, Pseudomonas aeruginosa, Klebsiella, Enterococcus, Enterobacter, Proteus and Serratia have been shown to be strongly associated with acute bacterial prostatitis and have been implicated as important risk factors for PCa development^112,113. In PCa patients, the relative abundance of several urinary bacteria with pro-inflammatory properties is significantly elevated, such as Staphylococcus, Ruminococcaceae, Neisseria, Streptococcus anginosus, Anaerococcus lactolyticus, Anaerococcus obesiensis, Actinobaculum schaalii, Varibaculum cambriense, Propionimicrobium lymphophilum, Veillonella, Streptococcus, Bacteroides, Fenollaria, Peptoniphilus, Anaerococcus, Porphyromonas and Fusobacterium^80,114–117. A parallel study also indicated that PCa patients have elevated urinary levels of Veillonella, Streptococcus, and Bacteroides, accompanied by significant reductions in Sphingomonas, Subdoligranulum, Blautia, Pseudomonas, Faecalibacterium, Lactobacillus, Acinetobacter, Clostridium, Lachnospira, and Acetanaerobac^115,118. Notably, procedures such as transrectal prostate biopsy also perturb the urinary microbiome. Pre-biopsy samples show higher Lactobacillus and Staphylococcus, whereas post-biopsy specimens demonstrate a decrease in Lactobacillus and an increase in Prevotella¹¹⁹.

The urinary microbes in PCa patients could be affected by therapeutic interventions, such as radiotherapy and ADT. For instance, PCa patients have a higher risk of urinary tract infections (UTIs) compared to healthy individuals; however, those undergoing radiotherapy or ADT exhibit a reduced incidence of UTIs¹²⁰. Radiotherapy markedly reduces the urinary microbiota. In urine samples collected from PCa patients, the most frequently isolated species before treatment included Staphylococcus haemolyticus, Staphylococcus epidermidis, Staphylococcus hominis, Enterococcus faecalis, and Micrococcus luteus. By the end of radiotherapy, there was a substantial reduction in the diversity and abundance of urinary microbiota, indicating treatment-induced depletion of the urinary microbial populations¹²¹.

In vitro studies demonstrate that uropathogenic Escherichia coli (UPEC) secretes cytotoxic necrotizing factor 1 (CNF1), which activates the Cdc42–PAK1 signaling pathway and promotes PCa progression¹²². The genitourinary microorganism Propionimicrobium lymphophilum promotes PCa cell proliferation by converting glucocorticoids into 11-oxy-androgens through the activity of the desAB gene, which encodes steroid-17,20-desmolase¹²³. It has also been found that isolates from urine were found to encode expression of the desG gene, which catalyzes the conversion of androstenedione to testosterone and thus promotes PCa cell growth by regulating steroid metabolism¹²⁴.

Intratumoral microbiota and prostate cancer

Unlike microbiota residing in other tissues or organs, tumor-resident microorganisms can interact directly with components of the tumor microenvironment, thereby influencing the initiation and progression of PCa (Fig. 2 and Table 2). Therefore, a precise characterization of tumor-resident microbiota is critical for understanding their functional mechanisms and informing the development of targeted interventions. However, as discussed above, accurately defining PCa–specific microbiota remains challenging due to technical limitations in sample collection and the precise measurement of microbial content in minimal tissue samples²⁰.

Fig. 2. Stage-specific presence of microorganisms and metabolic pathways during prostate cancer progression.

Prostatic epithelial cells are shown in purple, stromal cells in orange, and the basement membrane separating epithelial and stromal cells is shown in gray. Blue words represent metabolic pathways.

Table 2.

Summary of microbiome profiles during prostate cancer progression

Stage	Main microbiome profiles	Refs
Prostatic intraepithelial neoplasia	Prevotella	77
	Pseudomonas and Propionibacterium	130
	Cytomegalovirus	173
Invasive prostate cancer	Staphylococcus saprophyticus	128
	Propionibacterium	134
	Enterobacteriaceae	88
Castration-resistant prostate cancer	Escherichia	90
	Ruminococcus and Phascolarctobacterium	96
	Gemella and Lactobacillus	100
Metastasis	Klebsiella, Clostridium, Bacteroides, Lactobacillus, Streptococcus, Pseudomonas and Staphylococcus	99
	Ruminococcaceae	103

Early studies largely suggested that the presence of microbes in prostate tissue was unlikely, with any detected microbes generally attributed to inflammatory regions adjacent to prostate carcinoma¹²⁵. However, advances in high-throughput sequencing have begun to reveal tumor-resident microbiome. Multiple bacteria (i.e., Propionibacterium, Staphylococcus, Escherichia, Acinetobacter, Pseudomonas, Streptococcus and Methylophilus) and viruses such as Epstein–Barr virus (EBV) have been detected within prostate tumors, although no specific microorganism has been conclusively implicated in prostatitis and PCa and many of the candidate microbes appear to be uncultivable using standard laboratory methods¹²⁶. As indicated by 16S rRNA sequencing, compared with non-cancerous controls, prostate tumor tissues displayed significantly reduced microbial alpha diversity¹²⁷. Both PCa tissues and their noncancerous controls have overlapping genera, including Kocuria, Rhizophila, Nocardioides, Pseudonocardiaceae, Flavobacteriales, Streptophyta, Brunensis, Cibaria, Phyllobacteriaceae, Paracoccus, Rhodobacter and Rheinheimera perlucida. Interestingly, Varibaculum, Solirubrobacterales, Lactobacillaceae, Pediococcus, Skermanella and Erythrobacteraceae are unique to non-cancerous controls, whereas Defectiva, Cruenta, Aerolat, Clostridiaceae and Tissierellaceae are only presented in cancerous tissues¹²⁸. Notably, prostate tumors with stage T1 and T2 exhibited higher overall bacterial loads compared to T3 tumors. Staphylococcus saprophyticus was particularly enriched in T3-stage cancers, suggesting a pattern of selective microbial enrichment during PCa progression¹²⁸. However, the findings of another study using 16S rRNA gene sequencing differed significantly, reporting a reduction in microbial alpha diversity in PCa tissues¹¹⁷. Compared to benign prostatic hyperplasia, PCa samples contain a higher abundance of Cupriavidus taiwanensis, Methylobacterium organophilum, Brevundimonas vancanneytii, Neisseria flavescens, Acinetobacter junii, Bradyrhizobium cytisi, Cupriavidus basilensis, Caulobacter segnis, Leclercia adecarboxylata and Neisseria elongata, and a lower abundance of Kocuria palustris, Cellvibrio mixtus, Pseudomonas stutzeri, Paracoccus Staphylococcus hominis, Corynebacterium tuberculostearicum, Brachybacterium paraconglomeratum, Staphylococcus arlettae, Staphylococcus cohnii, Anaerococcus octhnii and Anaerococcus Octavius, as indicated by 16S rRNA sequencing. Further pathway analysis suggested that nitrotoluene degradation, steroid hormone biosynthesis, non-homologous end-joining and primary bile acid biosynthesis were associated with PCa. Additionally, the abundance of viral DNA from EBV, HBV, HPV16 and HPV18 was significantly higher in PCa samples¹²⁷. Collectively, as indicated by 16S rRNA sequencing, PCa samples show reduced microbial diversity, distinct bacterial compositions, and stage-specific shifts, with certain taxa enriched in cancerous versus non-cancerous tissues. Functional analyses link these changes to pathways in hormone and bile acid metabolism, while increased viral DNA (EBV, HBV, HPV16, HPV18) further highlights a complex microbial–viral landscape in PCa.

In addition to 16S rRNA sequencing, the microbiota within PCa tissues has also been characterized by using metagenomic and metatranscriptomic approaches. However, as previously discussed, these analyses face significant technical challenges, particularly in accurately distinguishing microbial sequences from host-derived sequences. By using of an array-based metagenomic and capture-sequencing approach, multiple types of microbiome signatures have been found in PCa tissues, including viruses, bacteria, fungi and parasites¹²⁹. Comparative analyses of prostate tumor samples from Africa, Australia and China revealed high abundances of Escherichia, Propionibacterium and Pseudomonas, with African and Australian cohorts showing particularly elevated bacterial loads. African specimens also exhibited increased Escherichia and Acidovorax levels¹³⁰. Analysis of the public dataset GSE115414 demonstrated that, relative to normal prostate tissue, cancer samples showed higher Shewanella, while Staphylococcus saprophyticus and Vibrio parahaemolyticus were significantly reduced. Notably, Shewanella abundance correlated inversely with Toll-like receptor signaling and dendritic cell infiltration¹³¹. Analysis of the microbiota in the TCGA-PRAD revealed the highest abundance of Bacillus, Pseudomonas, Paenibacillus, Acinetobacter and Corynebacterium⁹⁹. Comparative analysis of the microbiota between neuroendocrine PCa (NEPC) and prostate adenocarcinoma (AdPC) revealed distinct microbial profiles. NEPC exhibited a higher relative abundance of Escherichia, whereas Pseudomonas was more prevalent in AdPC¹³². Another study reported the presence of microorganisms in metastatic PCa. Notably, genera such as Staphylococcus, Streptococcus, Lactobacillus, Pseudomonas, Clostridium, Klebsiella, and Bacteroides were enriched in metastatic lesions. However, no significant differences in alpha- or beta-diversity were observed among samples from different metastatic sites⁹⁹. Similarly, RNA-seq analysis of radical prostatectomy specimens revealed that, compared to adjacent normal tissues, PCa samples exhibited a significant reduction in Bacteroides fragilis, Saimiriine betaherpesvirus, Staphylococcus saprophyticus, and Vibrio parahaemolyticus, accompanied by a marked enrichment of Shewanella¹³³. Microbiome profiling of Chinese radical prostatectomy samples demonstrated that both tumor and adjacent benign tissues were predominantly colonized by Escherichia, Propionibacterium, Acinetobacter, and Pseudomonas¹³⁴. Despite ongoing controversies surrounding the use of metagenomic and metatranscriptomic approaches to analyze tumor-resident microbiota, some findings from these methods corroborate results obtained through 16S rRNA sequencing and other microbiome-specific sequencing techniques.

Functionally, the abundances of Listeria monocytogenes, Methylobacterium radiotolerans JCM 2831 and Xanthomonas albilineans GPE PC73 were inversely correlated with Gleason score, tumor lymph node metastasis stage and PSA levels, respectively¹³⁵. High levels of Staphylococcus epidermidis and low levels of Streptococcus pneumoniae and Mannheimia haemolytica were closely associated with aberrant activation of the PI3K/AKT pathway and shifts in certain microbiome correlated significantly with the expression of stem cell markers SOX2, NANOG and CD44¹³⁶.

Propionibacterium is regarded as one of the most consistently reported microbes in PCa studies^137–140. The abundance of Propionibacterium is significantly elevated in PCa patients and positively correlates with cancer risk³². In parallel studies, Propionibacterium was detected only in PCa tissues but not in normal prostate tissues, as suggested by the analysis of RNA samples and in situ immunofluorescence^141,142. Furthermore, researchers have localized Propionibacterium within PCa tissue by multicolor fluorescence in situ hybridization (FISH), demonstrating persistent infection characterized by intracellular presence and biofilm-like aggregates in the stroma¹⁴³. Ultra-deep pyrophosphate sequencing of radical prostatectomy samples showed significant differences in the specific microbiota in the tumor, peritumor and non-tumor areas of the prostate, with Propionibacterium and Staphylococcus being significantly enriched in the tumor and its periphery, whereas Streptococcus was found predominantly in non-tumor tissues¹⁴⁴. In cases of aggressive PCa, 16S sequencing of DNA extracted from rapidly frozen tissues revealed that Propionibacterium was detected in 95% of samples¹⁴⁵. Strains of Propionibacterium isolated from human PCa induced persistent prostatitis when inoculated into murine models¹⁴⁶. In animal experiments, infection with the strain in the ventral and dorsal lobes of the mouse prostate resulted in significant focal inflammation in the dorsal lobe during chronic infection lasting up to 3 months¹⁴⁷. Co-culture of Propionibacterium with the prostate epithelial cell line PNT1A induces sustained secretion of IL-6 and CXCL8¹⁴⁸. In clinical samples, Propionibacterium isolates from tumors triggered robust inflammatory responses in RWPE-1 prostate epithelial cells by activating NF-κB and STAT3 pathways¹⁴². Similarly, Propionibacterium infection of RWPE-1 cells induced IL-6, IL-8 and GM-CSF secretion and upregulated the TLR2–NF-κB axis¹⁴⁹. Another study showed that Toll-like receptor 2 (TLR2) plays a key role in Propionibacterium-induced inflammatory response, a process that promotes the secretion of IL-6, IL-12 and IL-8 by activating the NF-κB signaling pathway¹⁵⁰. Moreover, Propionibacterium may contribute to the formation of an immunosuppressive microenvironment by recruiting Th17 and Treg cells and inducing the expression of immunosuppression related genes such as PD-L1, CCL17 and CCL18^151,152. Although accumulating evidence suggest a role of Propionibacterium in PCa progression, some studies have concerns about these associations between Propionibacterium and PCa, given that Propionibacterium is a well-known sequencing contaminant^153,154.

In addition to Propionibacterium, some other microbes have been also shown to induce inflammation in the prostate, thereby promoting PCa progression^155–159. For instance, Mycoplasma genitalium has been independently associated with an increased incidence of PCa and with more advanced disease stages¹⁵⁷. A history of multiple sexually transmitted infections or untreated infections appears to confer a particularly high risk for PCa development¹⁶⁰. However, other studies have reported that, although Mycoplasma genitalium is the most commonly detected pathogen across urine, glans swab, and prostatic tissue samples, no statistically significant association with PCa incidence has been observed¹⁶¹.

It is noteworthy that studies investigating different strains of the same bacterial species in PCa have yielded contradictory results. Uropathogenic Escherichia coli (CP1) isolated from human prostate induced chronic prostatitis and further accelerate the progression of PCa via urethral infection¹⁶². In a parallel study, urethral infection with CP9 also induced prostatitis in a mouse model, wherein cytotoxic necrosis factor 1 secreted by CP9 promoted the differentiation of basal cells into luminal cells, thereby accelerating the progression of PCa originating from basal cells¹⁶³. However, on the other hand, another study demonstrated that CP1 not only increased the rate of immunogenic cell death in PCa cells, but also promoted the infiltration of activated CD8⁺ T cells, Th17 cells, mature dendritic cells, M1-type macrophages, and natural killer (NK) cells within the tumor microenvironment, thereby enhancing the efficacy of PD-1 immunotherapy¹⁶⁴.

Current knowledge of nonpathogenic commensal fungi and viruses in PCa remains limited. Some studies have linked sexually transmitted infections caused by known pathogenic microbes to increased PCa risk^{155,165–167}. DNA from HPV and papilloma viruses has been detected in fresh-frozen prostate samples¹⁶⁸. HPV16 DNA has likewise been identified in both benign prostatic hyperplasia and PCa tissues^169–171. Chronic infection with HPV8 has been correlated with Th2 immune responses in PCa patients from Tobago and may facilitate tumor progression¹⁷². Another investigation identified human cytomegalovirus within premalignant and malignant prostate lesions. This virus was highly expressed in basal cell hyperplasia and prostatic intraepithelial neoplasia but downregulated in invasive carcinoma, implicating its potential role in early tumorigenesis¹⁷³. BK virus has been localized to PCa tissues by FISH, where it may induce tumor formation via large tumor antigen activity¹⁷⁴. JC virus has also been detected in fresh-frozen benign and malignant prostate samples¹⁷⁴. Immunohistochemical analyses have revealed EBV presence in PCa samples¹⁷⁵. PCR assays show high, comparable detection rates of HPV18 and EBV sequences across normal, benign and malignant prostate tissues¹⁷⁶.

Strategies employed by the microbiota in regulating prostate cancer

Traditionally, multiple intrinsic and extrinsic factors have been considered to contribute to the development of PCa. However, recent studies have revealed that microbiota residing in the gut, urinary tract, and prostatic tissue may also exert a non-negligible influence on the initiation and progression of this malignancy. Current studies have shown that a number of potential commensal and non-commensal microbiome and their metabolites can be involved in the regulation of PCa by modulating the tumor microenvironment or signaling pathways¹⁷⁷. In vitro studies have shown that infections with Mycoplasma genitalium and Mycoplasma hyorhinis can induce malignant transformation of BPH-1 cells, significantly enhancing their migration and invasion¹⁷⁸. Microbiome in the bloodstream have also been implicated in PCa. MR studies have revealed a potential causal relationship between serum levels of Epstein-Barr virus antibodies and increased risk of PCa¹⁷⁹. Plasma microbial 16S rDNA levels were significantly higher in patients with cancer recurrence compared to patients without recurrence after prostatectomy, suggesting that their translocation levels are strongly associated with postoperative recurrence¹⁸⁰. In addition, the study analyzed prostate secretions mainly enriched with Escherichia, Klebsiella, Shigella, Proteus, Enterobacter. The viruses JC Polyomavirus and HPV81 were also enriched in mixed samples of prostate secretions and urine¹⁸¹. Besides, certain microbiome and their products showed inhibitory effects on PCa. Salmonella typhimurium can invade PC-3 PCa cells and induce cell death¹⁸². Moreover, Serratia marcescens subsp. lawsoniana effectively induces PC-3 cell death and significantly reduces subcutaneous tumor volume in animal models following tail vein injection¹⁸³. Methanol extracts of Synechococcus have also demonstrated antiviral and antibacterial activities against PCa cell lines¹⁸⁴. Similarly, microbially derived phenylacetylglutamine can retard the progression of PCa¹⁸⁵.

Microorganism-derived metabolites and prostate cancer

Androgens

The androgen-androgen receptor (AR) signaling axis plays a central role in the initiation, progression, and treatment of PCa. Androgens bind to the AR to activate downstream signaling pathways, thereby promoting PCa development¹⁸⁶. Certain bacterial species serve as alternative sources of androgen biosynthesis, markedly compromising the therapeutic efficacy of ADT¹⁸⁷. According to the study, ADT promotes the expansion of specific commensal gut bacteria capable of converting androgen precursors into active androgens, thereby sustaining PCa growth and driving the development of castration-resistant disease^102,188,189. It has been shown that the Clostridium scindens can convert glucocorticoids, through its desAB gene encoding steroid-17,20-desmolase, into 11-oxy-androgens, thereby promoting the proliferation of PCa cells^123,190. The Clostridium scindens can also utilize the enzyme encoded by the desF gene to convert androstenedione to epitestosterone, which in turn accelerates the growth of PCa cells via the steroid metabolic pathway¹²⁴. Those findings suggests that microbes may represent an overlooked endogenous source of androgens.

LPS

LPS, a major component of the outer membrane of Gram-negative bacteria, can recognize specific cell membrane molecules and activate intracellular signal transduction^191,192. In PCa, LPS has been shown to induce the proliferation, migration, and invasion of PCa cells^193–195. Not any bacterial source of LPS promotes tumorigenesis and development due to differences in key regions of LPS from different strains¹⁹⁶. LPS isolated from Escherichia coli has been shown to activate the NF-κB signaling pathway in DU145 and MAT-LyLu cells, thereby significantly enhancing cell metastasis. Intraperitoneal injection of LPS markedly increased prostate tumor growth in mice, accompanied by liver metastasis¹⁹⁷. Similarly, LPS from Pseudomonas can activate the NF-κB pathway in BPH-1 cells, upregulate multiple inflammatory cytokines, promote cell proliferation and epithelial-mesenchymal transition and suppress apoptosis¹⁹⁸.

PAGln

Phenylacetylglutamine (PAGln) is a metabolite produced from dietary phenylalanine through gut microbiota metabolism. Studies have shown that PAGln can upregulate CCNG2 and block the Wnt/β-catenin signaling pathway, thereby suppressing the proliferation and metastasis of PCa¹⁸⁵. However, the cancer screening cohort studies reported that elevated PAGln levels were associated with an increased risk of lethal PCa^199,200. Therefore, the role of PAGln in PCa requires further validation.

Toxins

Biologically active toxins synthesized and released by microorganisms during growth and reproduction can induce host DNA double-strand breaks, genomic instability, and oncogenic mutations²⁰¹. Botulinum toxin A, produced by Clostridium botulinum, suppresses the growth and proliferation of LNCaP and PC-3 cells by promoting the phosphorylation of phospholipase A2²⁰². Staphylococcal enterotoxins can induce apoptosis of PC-3 cells by regulating the expression of long noncoding RNAs such as Gas5, PCA3, and NEAT1²⁰³. Interestingly, a study in Nigerian patients by Akinpelu et al. reported a higher prevalence of E. coli with colibactin gene expression in PCa samples compared with controls, although the difference did not reach statistical significance²⁰⁴. Nevertheless, the therapeutic application of bacterial toxins in PCa still has a long way to go.

Imidazole propionate

Previous studies have demonstrated a negative correlation between serum histidine levels and the risk of PCa mortality²⁰⁵. The gut microbiota can metabolize histidine into imidazole propionate. As the final product of histidine metabolism, imidazole propionate is thought to inhibit the NF-κB pathway²⁰⁶, the activation of which promotes PCa progression and contributes to therapeutic resistance^207,208. Moreover, evidence directly confirms that gut microbiota can regulate the levels of imidazole propionate, leading to upregulation of PDZK1 expression and inhibition of phosphorylation within the PI3K/AKT signaling pathway, ultimately suppressing the proliferation and migration of PC3 and DU145 PCa cells²⁰⁹.

SCFAs

Short-chain fatty acids (SCFAs) are an important class of metabolites produced by gut microbial fermentation and are widely involved in diseases related to chronic inflammation, cardiovascular disease and cancer^210,211. Studies have shown that SCFAs levels are significantly elevated in patient PCa^103,212. In a study of Japanese PCa patients, SCFAs-producing bacteria such as Rikenellaceae, Alistipes and Lachnospira were found to be significantly enriched in high-risk PCa cases²¹³. Ruminococcus can promote PCa progression through the production of SCFAs¹⁸⁸. The vitro experiments revealed that SCFAs enhance the migration and invasion of PCa cells by inducing autophagy triggered by TLR3 activation²¹². In a mouse study, SCFAs were found to stimulate PCa growth by elevating circulating insulin-like growth factor 1 in tumor-bearing mice, which in turn activates local MAPK and PI3K signaling pathways in the prostate²⁰⁶.

Microorganisms and microenvironment remodeling in prostate cancer

Inflammation

Inflammation induced by bacterial infection can cause DNA damage and mutations, thereby promoting the development of PCa^50,109. Several bacteria have been identified to induce prostatitis or to be associated with the condition^{49,90–93,95,214}. Extensive studies have demonstrated that Propionibacterium can induce persistent prostatitis^{146,215–217}. Other investigations have shown that Escherichia coli, Pseudomonas aeruginosa, Klebsiella, Enterococcus, Enterobacter, Proteus and Serratia are strongly associated with acute bacterial prostatitis^112,113.

Different affected immune cells

Prostate epithelial cells RWPE-1 were stimulated by Trichomonas vaginalis to produce IL-6, an inflammatory factor that promotes the proliferation of PCa cells by inducing the polarization of THP-1-derived macrophages to the M2 type²¹⁸. Some microbial metabolites also exhibit anticancer activity. The polyphenol metabolite urolithin A, produced by gut microbes, enhances NK cell-mediated cytotoxicity against tumor cells in the peripheral blood of PCa patients²¹⁹. CP1 can activate T cells and promote immune cell infiltration, thereby enhancing the efficacy of PD-1 immunotherapy¹⁶⁴.

Microorganisms and signaling pathways in prostate cancer

Oncogenic signaling pathways

Gut microbiome can regulate signaling pathways through metabolites that promote PCa progression^21,220,221. Numerous studies have shown that various microbial metabolites play critical roles in the initiation and development of PCa²²². Studies have shown that uropathogenic Escherichia coli secretes CNF1, which activates the Cdc42–PAK1 signaling pathway and promotes PCa progression¹²². In PCa patients, elevated levels of Staphylococcus epidermidis are closely associated with aberrant activation of the PI3K/AKT pathway¹³⁶. Certain resident microbiota can serve as alternative routes for androgen biosynthesis, thereby producing androgens during androgen-deprivation therapy and facilitating PCa progression¹⁰². In vitro studies have demonstrated that Propionibacterium isolated from PCa can activate the NF-κB and STAT3 pathways¹⁵⁰. Animal experiments revealed that microbial metabolite SCFAs can activate MAPK and PI3K signaling pathways, thereby promoting PCa growth²⁰⁶. Another microbial metabolite trimethylamine N-oxide (TMAO) has been shown to upregulate the p38/HMOX1 pathway, further accelerating PCa progression²²³. However, certain metabolites such as PAGln can inhibit PCa proliferation and metastasis by blocking the wnt/β-catenin signaling pathway¹⁸⁵. This highlights the indispensable role of the microbiome in PCa (Fig. 3).

Fig. 3. Microbiome communicate with prostate cancer cells through diverse signaling pathways.

SCFAs short-chain fatty acids, IMP imidazole propionate, IGF1 insulin-like growth factor 1, IGF1R insulin-like growth factor 1 receptor, TMAO trimethylamine N-oxide, LPS lipopolysaccharide, UPEC uropathogenic Escherichia coli, CNF1 cytotoxic necrotizing factor 1, PAGIn phenylacetylglutamine, ADT androgen deprivation therapy, AR androgen receptor.

Metabolic pathways in cancer cells

Microorganisms can also regulate host metabolic pathways through their intrinsic properties, thereby influencing the progression of PCa. An analysis of rectal swab samples from PCa patients revealed a significant enrichment of Bacteroides and Streptococcus, while metabolic pathways related to folate and arginine were markedly downregulated⁸¹. LEfSe analysis has revealed that the activity of C-terminal processing peptidase is significantly increased in PCa, along with upregulation of pathways involved in colanic acid building block biosynthesis⁷⁸. Notably, microbiota associated with folate, biotin, and riboflavin metabolism were underrepresented in PCa patients, whereas bacteria involved in carbohydrate metabolism were relatively more abundant²²⁴, suggesting a role of metabolism programming in gut-prostate axis. Notably, dietary factors may also influence PCa susceptibility by modulating gut microbiome. One MR study found that consumption of sugar-free carbonated beverages significantly decreased the abundances of Negativicutes and Selenomonadales in the gut, thereby contributing to a reduced risk of PCa²²⁵.

DNA damage repair

Microorganisms can also induce DNA damage and repair to promote the progression of PCa. Studies have shown that FMT from PCa donors can activate DNA damage repair pathways and facilitate PCa progression¹⁰¹. Shrestha et al. exposed LNCaP PCa cells to Escherichia coli strains that produce the genotoxin colibactin, which induces double-strand DNA breaks and may contribute to gene fusion events in PCa cells, thereby supporting a role for bacteria-derived toxins in PCa development²²⁶. Heat-inactivated Escherichia coli isolated and cultured from BPH tissue can also induce DNA damage in RWPE-1 and DU145 cells²²⁷.

Potential microorganism-based diagnostic and therapeutic strategies for prostate cancer

Above summaries underscore a significant role of microbiota in PCa. Recently, bacterial immunotherapies are designed to modulate gut microbiota^228–230, due to its pivotal role in shaping host responses to immunotherapy^231–234. Moreover, microbial diversity may underlie the heterogeneous effects of diet and nutrition on PCa^235,236. Pharmacologic and dietary interventions can alter both urethral and gut microbiota. Considering that prostate microbiota may partially originate from the urethra and gut, interventions targeting these microbial communities could influence the prostate microenvironment^237,238, thereby influencing the efficacy of these therapeutic interventions. Therefore, urinary and fecal microbiota hold promise not only as biomarkers for the early diagnosis of PCa but also as therapeutic targets through interventions such as dietary modulation, probiotics, prebiotics, and FMT^239–242.

Accumulating studies have tested the efficacy of microorganisms-based therapeutic strategies in PCa (Fig. 4). For instance, it has been shown that dietary supplementation with the long-chain fatty acid omega-3 (MAG-EPA) mitigated the progression of PCa in mice by decreasing the abundance of the gut microbe Ruminococcaceae and the levels of its metabolite butyrate²⁴³. Supplementation with phytochemical-rich food-specific capsules combined with a probiotic blend of five lactobacillus probiotics, prebiotic inulin and vitamin D inhibited PSA elevation and effectively intervene in PCa progression²⁴⁴. The oral probiotic strain Escherichia coli Nissle 1917, in combination with levofloxacin, helps to control symptoms and flare-ups in patients with chronic bacterial prostatitis while ensuring therapeutic safety²⁴⁵.

Fig. 4. Potential microbiota-based therapeutic strategies for prostate cancer.

Modulating the gut microbiota through diets enriched with specific components to improve disease outcomes; utilizing fecal microbiota transplantation as a therapeutic intervention; employing viral vectors for targeted delivery of therapeutic agents; and altering the microbial composition by increasing the abundance of microbes that suppress prostate cancer while reducing those that promote its progression. FMT fecal microbiota transplantation.

More specifically, Akkermansia muciniphila has been proven to inhibit PCa effectively. Abiraterone acetate, a medication used to treat PCa by reducing androgen production, has been shown to promote the enrichment of Akkermansia muciniphila, which in turn enhances the biosynthesis of vitamin K2—a compound known to inhibit prostate tumor growth²⁴⁶. The abundance of Akkermansia muciniphila has been positively correlated with clinical responses to immune checkpoint inhibitors. Oral administration of Akkermansia muciniphila in non-responsive mice significantly enhanced recruitment of CCR9⁺CXCR3⁺CD4⁺ T lymphocytes to the tumor site, through an IL-12-dependent mechanism that improved the efficacy of PD-1 blockade²⁴⁷. Additionally, the relative abundance of Akkermansia muciniphila was significantly lower in BPH patients compared to healthy controls and animal experiments have shown that oral administration of Akkermansia muciniphila significantly ameliorated prostate hyperplasia-like features²⁴⁸.

In an animal model of PCa with longitudinal monitoring of the gut microbiome, Akkermansiaceae were significantly enriched during the initial 3 weeks, followed by increased abundance of Bifidobacteriaceae at the second time point and Enterococcaceae at the final sampling. These temporal shifts in microbial composition were accompanied by upregulation of microbial gene pathways involved in steroid biosynthesis, as well as butirosin and neomycin biosynthesis. In contrast, microbiota associated with naphthalene degradation were depleted²⁴⁹. Analyses of both patients and corresponding animal models reveal distinct gut microbiome alterations between castration-resistant and hormone-sensitive PCa. Notably, oral antibiotic administration resulted in depletion of commensal bacteria, which impaired the efficacy of ADT and was associated with a marked reduction in thymocyte proliferation and output²⁵⁰. Moreover, studies have shown that supplementing mice drinking water with broad-spectrum antibiotics profoundly disrupts microbial homeostasis, leading to Proteobacteria blooms and accelerated growth of both subcutaneous and prostatic tumors. Elevated intratumoral LPS levels promote PCa cell proliferation and driving docetaxel chemoresistance²⁰⁷.

Oral administration of some beneficial ingredients may modulate the gut microbiota to improve prostatitis. Poria cocos polysaccharides can attenuate CNP by targeting the gut microbiota²⁵¹. Daily gavage of Berberine hydrochloride altered the gut microbiome in rats, increased the abundance of Clostridium butyricum, reduced inflammation and oxidative stress in the prostate and effectively treated CP/CPPS²⁵². Oral astaxanthin likewise increases intestinal Akkermansia muciniphila and elevates serum SCFAs, leading to symptomatic improvement in chronic prostatitis²⁵³.

On the other hand, intratumoral microbiota is being investigated as a potential therapeutic target for the prevention, diagnosis and treatment of PCa. For instance, Escherichia produced TNF-α in mouse prostate tumors locally, inducing apoptosis of tumor cells²⁵⁴. Mammalian orthoreovirus (MRV), an oncolytic virus targeting tumor cells, induces apoptosis of PCa cells under hypoxic conditions by activating caspase-8 and caspase-9, downregulating HIF-1α expression, and subsequently reducing AKT and androgen receptor activities as well as PSA expression, thereby inhibiting PCa progression^255,256. Some studies have also revealed that microbes such as Mycoplasma genitalium, Staphylococcus, and Clostridium may serve as candidate biomarkers for early detection^144,157,257. Klebsiella, Lactobacillus, Bacteroides and Akkermansia may function as candidate prognostic markers for treatment outcomes^{98,250,258,259}.

While promising, microorganism-based therapies for PCa remain limited. Whether microbiota can serve as reliable diagnostic markers or therapeutic strategies for metastatic PCa is still an open question. Additionally, concerns have been raised that prolonged or excessive antibiotic use may increase the risk of developing PCa²⁶⁰. The application of non-pathogenic bacteria to specifically target tumor cells also faces limitations, primarily due to the potential for serious side effects²⁶¹.

Conclusions and perspectives

The intricate interplay between the host and its resident microbiota is increasingly recognized as a critical regulator of health and disease, exerting profound effects on PCa initiation and progression. In recent years, accumulating evidence has highlighted significant progress in characterizing the microbiota associated with PCa and in the preliminary exploration of its underlying molecular mechanisms. Distinct microbial communities originating from specific anatomical sites, such as the gut, urinary tract, and prostate tissue, are increasingly believed to be associated with PCa development (Fig. 1). Using samples from PCa patients and animal models, several studies have revealed distinct differences in specific microbiota across various stages of PCa (Fig. 2). These findings provide a scientific foundation to explore how stage-specific microbiota contributes to the regulation of cellular metabolism, immune modulation, and tumor progression.

Microorganisms have been shown to promote or inhibit the progression of PCa through various molecular mechanisms, including modulation of the Wnt/β-catenin, NF-κB, STAT3, p38/HMOX1, MAPK, and PI3K/AKT signaling pathways (Fig. 3). More interestingly, microbial metabolites, such as androgens and SCFAs, play a critical role in modulating the prostate tumor microenvironment. As integral components of tumor microenvironment, microbiota engage in dynamic communication with the host and profoundly influence PCa progression. Therefore, in the development of pathway-targeted therapies, the concurrent elimination of pathogenic microbes and their bioactive metabolites (e.g., SCFAs) may enhance therapeutic efficacy, offering a promising rationale for combination treatment strategies.

Given the direct regulatory roles of microbes within the tumor microenvironment, microbe-based therapies are being actively developed for PCa. Beyond conventional oral antibiotics, innovative strategies such as membrane-permeable antibiotics and nanoparticle-encapsulated formulations have been introduced to selectively eradicate tumor-associated bacteria and enhance therapeutic efficacy. The precise elimination of tumor-promoting microbes through genetically modified bacteriophages represents another promising avenue for targeted microbiota modulation. The studies reviewed herein highlight the therapeutic potential of targeting oncogenic microbes (i.e., Propionibacterium acnes, Escherichia, Staphylococcus, Acinetobacter, Pseudomonas). Conversely, enhancing the abundance of beneficial commensals such as Akkermansia muciniphila may provide novel strategies to improve PCa outcomes. Additionally, tumor-specific microbial traits have been harnessed to bioengineer bacteria capable of delivering prodrugs or cytotoxic agents directly into tumor cells, enabling highly selective cytotoxicity of cancer cells (Fig. 4).

Although certain PCa-associated microbes hold promising clinical potential, extensive and rigorous preclinical validation is essential prior to clinical translation. This includes the establishment of robust microbial biomarkers, comprehensive elucidation of underlying mechanisms, and the development of microbiome-informed adjuvant therapies aimed at overcoming therapeutic resistance and minimizing toxicity. Furthermore, considering the substantial interindividual variability in microbial composition, integrating multi-omics data, encompassing genomics, transcriptomics, proteomics, and metabolomics, from both host and microbiota will be critical. Such integration will facilitate the design of precision prevention and treatment strategies tailored to each patient’s unique microbial and molecular landscape, paving the way for more effective and personalized patient management.

Author contributions

X.D. and J.W. collected the information, wrote and revised the manuscript. S.X., H.Z., B.Z. provided overall guidance, designed and supervised the project. B.Z. revised and finalized the manuscript. All authors have read and approved the final manuscript.

Data availability

No datasets were generated or analyzed during the current study.

Competing interests

The authors declare no competing interests.