Microbial Therapeutics in Cancer: Translating Probiotics, Prebiotics, Synbiotics, and Postbiotics From Mechanistic Insights to Clinical Applications: A Topical Review

ABSTRACT

The gut microbiome plays a pivotal role in cancer development, progression, and treatment response, driving interest in microbiome‐based interventions. This review examines probiotics, prebiotics, synbiotics, and postbiotics (PPSPs) as precision tools in oncology, highlighting their mechanisms, clinical applications, and challenges. Gut microbiota influence cancer through immune modulation, metabolic regulation, and inflammatory control, while also shaping chemotherapy pharmacokinetics and immunotherapy efficacy. PPSPs demonstrate antitumor effects via: (1) immune activation, (2) intestinal barrier reinforcement, (3) pathogen suppression, and (4) carcinogen neutralization. Clinically, probiotics/postbiotics reduce chemotherapy‐induced mucositis and enhance checkpoint inhibitor responses, while synbiotics/prebiotics selectively nourish beneficial microbes. Despite promise, hurdles like strain‐specific variability, dosing optimization, and individual microbiome differences hinder translation. By integrating preclinical and clinical data, this review underscores PPSPs' potential to bridge gut ecology with antitumor immunity, advancing precision oncology. Future priorities include large‐scale trials, standardized protocols, and mechanistic insights into host‐microbiome‐cancer crosstalk. Personalized microbiota therapies, engineered consortia, and combination regimens represent promising frontiers. With robust evidence, PPSPs may emerge as essential adjuvants, improving outcomes while minimizing toxicity in cancer care.

This graphical abstract illustrates the multifaceted roles of probiotics, prebiotics, synbiotics, and postbiotics in cancer prevention and therapy. Key mechanisms include modulation of the gut microbiome, immune system regulation, enhancement of gut barrier function, and direct anti‐cancer activities like apoptosis induction and carcinogen inactivation. These bioactive compounds also support cancer therapy by reducing inflammation, neutralizing toxins, and serving as potential adjuvants to conventional treatments.

Abbreviations

Akt

(Protein kinase B)

BAX

(BCL2‐associated X protein)

BCL‐2

(B‐cell lymphoma 2)

CRC

(Colorectal cancer)

EPS

(Exopolysaccharides)

FAO

(Food and Agriculture Organization)

FAS

(Fas cell surface death receptor)

FOS

(Fructooligosaccharides)

GI

(Gastrointestinal)

GOS

(Galactooligosaccharides)

HCC

(Hepatocellular carcinoma)

HDAC

(Histone deacetylase)

IL

(Interleukin)

ISAPP

(International Scientific Association for Probiotics and Prebiotics

NF‐κB

(Nuclear factor kappa‐light‐chain‐enhancer of activated B cells)

NK

(Natural killer)

PD‐L1

(Programmed death‐ligand 1)

PI3K

(Phosphoinositide 3‐kinase)

PPSPs

(Probiotics, prebiotics, synbiotics, postbiotics)

ROS

(Reactive oxygen species)

SCFAs

(Short‐chain fatty acids)

SIRT1

(Sirtuin 1)

TLR

(Toll‐like receptor)

TNF‐α

(Tumor necrosis factor‐alpha)

WHO

(World Health Organization)

Wnt

(Wingless‐related integration site)

XOS

(Xylooligosaccharides)

1. Introduction

Anticancer‐antibiotics play a key role in the discussion of the microbiome and cancer because of their dual modes of action. Besides their well‐known function as modulators of the microbiome, several antibiotics are also standard chemotherapeutic agents. For instance, drugs such as doxorubicin, bleomycin, and mitomycin act as intercalating agents that directly damage cancer cell DNA and interfere with survival pathways [1, 2, 3]. This direct cytotoxic activity emphasizes their importance in oncology. However, their systemic administration also reveals a crucial interaction: by simultaneously disrupting the microbiome, antibiotics may paradoxically impair a patient's response to treatment, potentially increasing cancer risk and highlighting the complex relationship between these interconnected biological systems [4].

The past two decades have ushered in a transformative era in cancer treatment, fueled by breakthroughs in molecular biology, immunology, and nanotechnology. Targeted therapies, including monoclonal antibodies, kinase inhibitors, and adoptive cell therapies, have redefined precision medicine [5, 6]. Despite these advancements, therapy resistance continues to pose a major challenge, primarily driven by: (1) tumor‐intrinsic factors such as neoantigen depletion, disrupted immune signaling, and epigenetic reprogramming; and (2) acquired resistance mechanisms, including antigenic drift, clonal selection, and remodeling of the immunosuppressive tumor microenvironment. The complex interplay between tumor heterogeneity and clonal evolution highlights the necessity for multifaceted therapeutic strategies that concurrently target malignant cells and their surrounding ecological niche [7, 8, 9, 10, 11].

The gut microbiome has a dual impact on cancer, influencing both its development and treatment through mechanisms like inflammation, immune regulation, metabolism, and genotoxicity [12]. A healthy microbiome is critical for overall health, yet dysbiosis, a change in gut microbial equilibrium, has emerged as a major driver of cancer development, despite the fact that certain microbial profiles provide protective benefits [13, 14]. Dysbiosis, defined as an imbalanced gut microbiota, is at the root of many disorders. The main pathogenic processes are reduced intestinal barrier integrity, persistent inflammation, immunological dysfunction, and metabolic abnormalities. These activities disturb linked systems such as the gut‐brain and gut‐liver axes, exacerbating systemic dysfunction and driving disease development [15, 16].

Gut microbiota contribute to oncogenesis through three primary pathways: (1) metabolic regulation via microbial‐derived compounds such as short‐chain fatty acids (SCFAs) that directly impact tumor cell dynamics; (2) immune system modulation through bacterial‐mediated T‐cell differentiation and cytokine production; and (3) biotransformation of pharmaceutical agents that alters drug bioavailability and efficacy [17, 18, 19, 20, 21, 22]. These mechanisms highlight the microbiome's dual role as a driver of oncogenesis and a modulator of treatment response (Figure 1), offering avenues for biomarkers and microbiota‐targeted therapies [22, 23, 24].

FIGURE 1.

The gut microbiome: a double‐edged sword in cancer.

In contrast to conventional antibiotics that disrupt microbial balance, biointervention strategies aim to restore equilibrium by introducing beneficial microorganisms or suppressing pathogenic ones [11]. Precision microbiome interventions—including probiotics, prebiotics, synbiotics, and postbiotics (collectively termed PPSPs)—provide targeted approaches to microbial manipulation [25, 26]. Despite these advances, critical challenges hinder translation, including strain‐specific variability, interindividual microbiome differences, undefined dosing protocols, and an incomplete understanding of microbe–host–drug interactions. Safety assessments, especially for combination therapies in immunocompromised patients, remain a pressing need [27, 28]. To close existing gaps, microbiome research must be systematically integrated into precision oncology through rigorous clinical trials, followed by the discovery of strong biomarkers for patient classification. Overcoming these hurdles could unlock the full potential of PPSPs, allowing revolutionary microbiome‐driven techniques for cancer therapy. This expanding understanding has positioned microbiota‐targeted medicines as promising adjuvants in cancer treatment [29, 30].

This review critically evaluates the emerging roles of PPSPs in cancer prevention and treatment, emphasizing their mechanisms of action, applicability to specific cancer types, current limitations, and future prospects. We analyze PPSPs as multifaceted therapeutic agents that target cancer through immune, metabolic, and molecular pathways. These dual‐purpose tools hold promise not only for enhancing conventional cancer therapies but also for offering preventive benefits, positioning them as transformative additions to oncology's evolving landscape.

2. Methodology (Review Protocol)

This narrative review employed a rigorous, systematic approach to identify and evaluate the current evidence on microbial therapeutics in oncology. The methodology was designed to comprehensively assess the role of probiotics, prebiotics, synbiotics, and postbiotics in cancer prevention and treatment through critical analysis of published literature in peer reviewed. Journals.

2.1. Search Strategy: Terminology and Databases

A targeted literature search was conducted across multiple databases to ensure broad coverage of relevant studies. The search strategy involved querying PubMed, Scopus, Web of Science, and Google Scholar using relevant free‐text keywords. These included terms related to interventions (“probiotics,” “prebiotics,” “synbiotics,” “postbiotics,” “microbiome modulation”), diseases (“cancer,” “neoplasms,” “oncology”), and outcomes (“prevention,” “treatment efficacy,” “immunotherapy,” “tumor microenvironment”).

2.2. Study Selection Criteria

2.2.1. Inclusion Criteria

The search focused on publications in the English language, with an emphasis on studies from 2010 to 2024 to capture the most recent definitions, mechanistic insights, and current applications. Eligible study types included original research, clinical trials, meta‐analyses, and systematic reviews. The selection prioritized articles with direct relevance to microbial therapeutics in cancer, such as probiotics, prebiotics, synbiotics, postbiotics, and microbiome modulation. Only English‐language publications were considered to ensure consistency in data interpretation.

2.2.2. Exclusion Criteria

Studies excluded from the analysis comprised case reports, editorials, non‐English language articles, and sources lacking peer review. Additionally, duplicate publications were removed to ensure the originality and reliability of the selected research

3. Definition of Probiotics, Prebiotics, Synbiotics, and Postbiotics

3.1. Definition and Core Concepts of Probiotics

Probiotics, defined by the FAO/WHO as “live microorganisms that confer health benefits when administered in adequate amounts,” play a crucial role in maintaining gut microbiota balance. Strains like Lactobacillus, Bifidobacterium, and Saccharomyces have demonstrated potential in cancer prevention and therapy by modulating immune responses, reducing inflammation, and enhancing gut barrier integrity [29, 31]. Emerging evidence highlights the strain‐specific anticancer potential of probiotics like Lactobacillus and Bifidobacterium, though efficacy and safety require careful evaluation [27, 30].

3.2. Definition and Core Concepts of Prebiotics

Prebiotics are unique dietary components that selectively feed beneficial gut bacteria through fermentation [28]. By acting as fuel for these microbes, they help maintain a healthy and diverse gut microbiome [32]. As prebiotics pass undigested into the colon, gut bacteria break them down, generating SCFAs. These SCFAs play a crucial role in strengthening gut barrier function, regulating immunity, and supporting metabolic health. Additionally, prebiotics promote microbial balance, enhancing digestive wellness and contributing to broader physiological benefits. These SCFAs, such as acetate, propionate, and butyrate, serve as an energy source for colon cells (colonocytes) and contribute to various health benefits [33, 34].

Additionally, prebiotics help shape the composition and function of gut bacteria, favoring the growth of beneficial strains like Bifidobacterium and Lactobacillus. Unlike probiotics, which are live microorganisms, prebiotics are nondigestible fibers that act as fuel for beneficial bacteria [35, 36]. Common types of prebiotics include inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS), and resistant starches. These compounds resist digestion in the upper gastrointestinal tract, allowing them to reach the colon intact, where gut bacteria metabolize them [37, 38].

To qualify as a prebiotic, a substance must resist digestion, be fermented by gut bacteria, and selectively promote beneficial strains like Bifidobacterium and Lactobacillus. This targeted modulation of gut microbiota distinguishes prebiotics from general dietary fibers and supports gut health, immune function, and cancer prevention. Prebiotics like inulin and FOS meet these criteria by fostering beneficial microbial activity and producing SCFAs, which mediate their systemic health effects [39, 40].

3.3. Definitions and Core Concepts of Synbiotics

Synbiotics are strategically designed therapeutic formulations that combine probiotics (live beneficial microorganisms) with prebiotics (selectively fermented substrates) to produce synergistic health benefits [41, 42]. There are four potential examples of specific synbiotic agents: 1) Lactobacillus rhamnosus GG + Inulin [43, 44]; 2) Bifidobacterium longum  + FOS [45, 46]; 3) Lactobacillus casei Shirota + GOS [47, 48]; 4) Lactobacillus acidophilus  + Inulin [49, 50].

3.4. Definition and Key Characteristics of Postbiotics

Postbiotics are nonviable microbial preparations or their structural components that provide physiological benefits to the host, distinguishing them from purified microbial metabolites. These bioactive substances are generated either through controlled probiotic fermentation or via natural bacterial cell disintegration. The term broadly encompasses microbial fermentation products and related derivatives, including metabolites, SCFAs, microbial cell fractions, functional proteins, extracellular polysaccharides (EPS), cell lysates, teichoic acids, peptidoglycan‐derived muropeptides, and pili‐like structures. As a relatively recent addition to the “‐biotics” field, postbiotics are increasingly recognized for their functional and therapeutic potential [51, 52]. These compounds encompass several key categories: SCFAs like butyrate, acetate, and propionate; structural microbial components such as peptidoglycans and teichoic acids; functional proteins and peptides like bacteriocins and enzymes; as well as various other metabolites, including vitamins and organic acids. The International Scientific Association for Probiotics and Prebiotics defines postbiotics as preparations of inanimate microorganisms and/or their components that confer health benefits on the host, emphasizing their broad scope beyond metabolites alone [53, 54]. These nonviable microbial derivatives, particularly SCFAs, cell wall fragments, peptides, and metabolic byproducts, are revolutionizing therapeutic approaches in fields ranging from oncology to immunology [55]. Their distinct advantage lies in their superior stability compared to live probiotics, consistent pharmacological activity, and enhanced safety profile, especially crucial for immunocompromised patients who may face risks from live microbial treatments. By delivering targeted biological effects without requiring viable organisms, postbiotics represent a significant advancement in microbiome‐based medicine, offering precise therapeutic interventions while overcoming many limitations of traditional probiotic therapies [56, 57].

4. Key Mechanisms of Probiotics, Prebiotics, Synbiotics, and Postbiotics in Cancer Prevention and Treatment

4.1. Probiotics

Commercially, Lactobacillus and Bifidobacterium are the most widely used probiotic genera [58, 59]. Their primary anticancer effects are outlined as follows: 1) Probiotics reduce tumor‐promoting cytokines (TNF‐α, IL‐6) and increase the anti‐inflammatory cytokine IL‐10, thereby alleviating chronic inflammation that contributes to carcinogenesis [60, 61]; 2) Specific probiotic strains bind and neutralize dietary mutagens (such as heterocyclic amines from cooked meats), decrease their absorption in the intestine, and inhibit bacterial enzymes (β‐glucuronidase, nitroreductase) responsible for producing carcinogens [62, 63]; 3) Microbial metabolites such as butyrate, acetate, and propionate trigger apoptosis by modulating the Bax/Bcl‐2 ratio and releasing cytochrome‐c; 4) Triggering mitochondrial dysfunction through reactive oxygen species (ROS) induction [64, 65]; 5) Suppressing HDAC activity and restoring the function of tumor suppressor genes [64, 66]; 6) Downregulating SIRT1 and PI3K/Akt/mTOR signaling [66, 67]; 7) activating caspases and extrinsic Fas/FasL pathways; 8) Exploiting cancer metabolic reprogramming (Warburg effect) [67, 68]; 9) Probiotics enhance tight junction integrity, stimulate mucin secretion, and competitively exclude pathogens, thereby reducing inflammation and infection‐driven carcinogenesis [69, 70]; 10) They promote NK cell cytotoxicity [71, 72], dendritic cell maturation, macrophage activity, and CD8+ T‐cell responses [73], thereby strengthening anti‐tumor immunity [60, 74]; 11) Probiotics enhance microbial diversity, decrease carcinogen production, and preserve gut homeostasis by promoting beneficial microbes and inhibiting pathogens linked to dysbiosis [75, 76].

4.2. Prebiotics

Prebiotics are nondigestible fibers that selectively stimulate the growth of beneficial gut bacteria, primarily Bifidobacterium and Lactobacillus. Their mechanisms of action include: 1) Fermentation produces short‐chain fatty acids (SCFAs), especially butyrate, which regulate cell proliferation, differentiation, apoptosis, and epigenetic modifications [77, 78]; 2) SCFAs influence regulatory T‐cells, suppress pro‐inflammatory cytokines, and boost tumor immune surveillance [64, 79]; 3) Prebiotics enhance tight junction protein expression, stimulate mucus secretion, and decrease carcinogenic secondary bile acids [80, 81, 82]; 4) They induce apoptosis in malignant cells via HDAC inhibition [83, 84], neutralize carcinogens, inhibit angiogenesis, reduce oxidative stress, and modulate host metabolism, lowering the risk of obesity‐related cancers (131, 132); 5) Prebiotics may also enhance chemotherapy effectiveness, lessen treatment toxicity, and help overcome drug resistance via microbiome‐related mechanisms [85, 86, 87].

4.3. Synbiotics

Synbiotics combine probiotics and prebiotics, yielding synergistic benefits beyond their individual effects. Their key mechanisms of action include: 1) Stabilize microbial diversity, enrich Lactobacillus and Bifidobacterium, and suppress dysbiosis, lowering cancer risk [88, 89]; 2) enhance NK cell, macrophage, and Treg activity, reduce pro‐inflammatory cytokines, and promote SCFA‐mediated HDAC inhibition, leading to apoptosis and oncogene suppression [65, 90]; 3) bind mutagens, suppress bacterial procarcinogenic enzymes, induce apoptosis, inhibit angiogenesis, and even modulate hormone‐driven cancers [91, 92]; 4) alleviate treatment‐related side effects (e.g., mucositis, dysbiosis, fatigue) and may improve responses to immunotherapies [93]. The distinct yet complementary roles of probiotics, prebiotics, and synbiotics components are compared across key anticancer mechanisms in Figure 2, highlighting how synbiotics leverage the direct actions of probiotics and the indirect, microbiota‐mediated support of prebiotics for an amplified therapeutic outcome.

FIGURE 2.

Six shared mechanisms for the anticancer effects of probiotics, prebiotics, and synbiotics. The chart delineates the distinct and complementary contributions of each component across key physiological processes, including immune modulation and carcinogen.

4.4. Postbiotics

Postbiotics are microbial metabolites and cell components with direct bioactivity. Their key mechanisms include: 1) SCFAs and exopolysaccharides (EPS) reduce pro‐inflammatory cytokines, enhance IL‐10, and promote gut barrier stability [94, 95]; 2) They trigger apoptosis (via caspase activation, Bax upregulation, Bcl‐2 suppression), induce cell cycle arrest, and inhibit angiogenesis. EPS also exhibit selective cytotoxicity and enhance immune responses [96, 97]; 3) By strengthening the gut barrier and enhancing detox enzymes, postbiotics reduce nitrosamine absorption and toxicity [98, 99]; 4) Postbiotics mitigate chemotherapy‐ and radiotherapy‐induced side effects, protect tissues from oxidative stress, aid surgical recovery, and may improve immunotherapy outcomes [100, 101]. The functional relationship between these components is illustrated in Figure 3, which outlines how the fermentation of prebiotics by probiotics yields postbiotic metabolites (e.g., SCFAs) that are directly responsible for critical anticancer processes such as HDAC inhibition and immune activation via Toll‐like receptors (TLRs).

FIGURE 3.

The functional workflow of prebiotics, probiotics, and their resulting postbiotics in mediating anticancer activity. Prebiotics serve as substrates for probiotics, which ferment them into bioactive postbiotics (e.g., SCFAs). These metabolites directly induce apoptosis, enhance the gut barrier, and modulate immune responses through specific molecular pathways like HDAC inhibition, demonstrating benefits that can be delivered even by cell‐free components.

5. Potential Applications of Probiotics, Prebiotics, Synbiotics, and Postbiotics in Cancer Prevention and Therapy

Mounting evidence emphasizes the critical role of gut and oral microbiota in shaping cancer risk and treatment responses [102]. PPSPs have emerged as promising strategies to modulate microbial ecosystems, enhance host immunity, and counteract carcinogenic processes across multiple cancers. These microbial modifiers help maintain a balanced microbiome, promote beneficial bacteria growth, and influence immune responses that can suppress tumor progression, induce apoptosis, and reduce inflammation. Additionally, they have adjunctive potential in cancer therapy by reducing treatment side effects and improving therapeutic efficacy through immunomodulation and metabolic regulation [103].

In colorectal cancer (CRC), probiotics such as Lactobacillus and Bifidobacterium strains enhance SCFA production, improve intestinal barrier integrity, and suppress inflammatory signaling: Studies demonstrate that probiotics including Lactobacillus acidophilus and Bifidobacterium bifidum increase SCFA production, which nourishes colonocytes and strengthens gut barrier function, reducing colonic inflammation and carcinogen exposure [104, 105]. These effects reduce exposure to carcinogens, promote apoptosis in malignant cells, and enhance responsiveness to chemotherapy while mitigating gastrointestinal side effects: Probiotics reduce carcinogen bioavailability by binding and degrading mutagens, induce apoptosis of colorectal tumor cells, and support immune modulation to improve chemotherapy efficacy and reduce its side effects like diarrhea [106, 107]. Prebiotics like inulin, FOS, and GOS amplify these benefits by fueling butyrate production, which exerts anti‐inflammatory and tumor‐suppressive effects. Whole‐food fiber intake appears consistently protective, while synbiotics combine both approaches synergistically, improving treatment tolerance and reducing systemic inflammation [108, 109]. Postbiotics, particularly butyrate, further contribute by inducing apoptosis, modulating immune activity, and restoring microbial balance, making them promising adjuvants in CRC therapy. Butyrate has been shown to inhibit proliferation and induce apoptosis of CRC cells through mechanisms involving cell cycle disruption and activation of apoptotic pathways. It also modulates immune responses and helps restore intestinal microbial homeostasis, enhancing gut barrier function and reducing tumor progression. Various studies highlight the role of postbiotics and their metabolites in improving CRC treatment outcomes and alleviating chemotherapy‐induced gut dysbiosis [110, 111].

Similar protective mechanisms are evident in hormone‐driven cancers such as breast and prostate malignancies. By regulating β‐glucuronidase activity, probiotics and prebiotics reduce systemic estrogen reabsorption, lowering the risk of estrogen receptor–positive breast cancer. High dietary fiber intake has consistently been associated with lower breast cancer incidence, and synbiotics appear to alleviate treatment‐related inflammation and dysbiosis [112, 113]. Postbiotic metabolites such as equol and enterolactone show theoretical promise in modulating estrogen and androgen pathways, though clinical data remain limited [114, 115].

In gastric cancer, microbiota‐targeted strategies act primarily through infection control and inflammation reduction. Probiotics and synbiotics suppress Helicobacter pylori colonization and its associated gastritis, a precursor of gastric cancer, by enhancing mucosal immunity, reducing oxidative stress, and strengthening the gastric mucosal barrier. Postbiotics like bacteriocins exhibit direct antimicrobial activity against H. pylori [116, 117].

In hepatocellular carcinoma, interventions along the gut–liver axis reduce lipopolysaccharide translocation, modulate bile acid metabolism, and alleviate fibrosis, key steps in hepatocarcinogenesis. These interventions include probiotics, fecal microbiota transplantation, and antibiotic therapy to improve gut microbial balance and liver health [118, 119]. SCFAs and related postbiotics additionally regulate tumor suppressors and counteract oncogenic pathways, underscoring their potential as adjunctive therapies in these cancers [116, 120].

In bladder and oral cancers, probiotics and prebiotics promote immune surveillance, suppress pathogenic microbes, and attenuate chronic inflammation. Studies in bladder cancer demonstrate that probiotics such as Lactobacillus casei reduce tumor recurrence and modulate the immune response.

Synbiotics help restore microbial balance disrupted by cancer therapies and may potentiate immune checkpoint inhibitor activity by improving gut and systemic immunity. Postbiotics, including EPS and tryptophan‐derived metabolites, are under investigation for enhancing immunotherapy efficacy in resistant tumors like melanoma and non‐small‐cell lung cancer, showing immunomodulatory and tumor‐suppressive effects [121, 122].

Collectively, these findings highlight the multifaceted potential of microbiota‐directed interventions in cancer prevention and therapy. While preclinical and translational data are compelling, clinical validation remains limited for many cancer types. Future studies should focus on identifying optimal strains, prebiotic substrates, and metabolite formulations, alongside precision approaches tailored to host–microbiome interactions. Representative applications of probiotics, prebiotics, synbiotics, and postbiotics across different cancer types, along with their mechanisms, evidence level, and status, are summarized in Table 1.

TABLE 1.

Representative applications of probiotics, prebiotics, synbiotics, and postbiotics in cancer prevention and therapy.

Cancer type	Intervention	Key findings/effects	Evidence level	Current status	Ref
Colorectal cancer	Probiotic ( Lactobacillus rhamnosus GG)	Reduced tumor incidence; improved mitochondrial function; enhanced anti‐tumor immunity	Preclinical + translational	Ongoing experimental use	[44, 123]
	Postbiotics (Butyrate, SCFAs, microbial metabolites)	Induced apoptosis; inhibited proliferation; regulated Wnt signaling; reduced inflammation	Preclinical + early clinical	Translational/experimental	[124]
Breast cancer	Prebiotic (Inulin)	Inhibited tumor growth; slowed progression; enhanced SCFA production; reduced inflammation	Preclinical (animal models)	Early‐stage experimental	[125]
	Postbiotics (Propionate, microbial peptides)	Anti‐proliferative; altered gene expression; immune modulation	Preclinical	Under investigation	[126]
Liver cancer (HCC)	Synbiotic (Bifidobacterium + inulin)	Suppressed inflammation; improved liver function; restored microbiota balance	Preclinical + reviews	Early‐stage evidence	[127, 128]
	Postbiotics (Urolithins, bile acid modulators)	Reduced liver injury; attenuated tumor‐promoting inflammation; modulated oxidative stress	Preclinical	Experimental	[129]
Gastric cancer	Probiotic ( Lactobacillus casei , others)	Reduced H. pylori ‐induced inflammation and oxidative stress; improved gastritis	Preclinical	Studied but not approved	[130, 131]
	Postbiotics (Bacteriocins, peptidoglycans)	Inhibited H. pylori ; reduced gastric inflammation; immune‐modulating effects	Preclinical. In vitro	Exploratory stage	(161–163)
Bladder cancer	Probiotic supplementation	Enhanced immune surveillance; improved efficacy of BCG immunotherapy; lowered recurrence risk	Preclinical + early clinical	Preliminary evidence	(164–167)
	Prebiotic/SCFA metabolites (e.g., butyrate)	Induced apoptosis in urothelial cells; activated tumor suppressors	Preclinical	Under study	(71, 168, 169)
Oral cancer	Probiotics (Lactobacillus, Bifidobacterium)	Balanced oral microbiota; suppressed pathogenic bacteria; reduced chronic inflammation	Preclinical + observational	Limited clinical data	(170–173)
	Prebiotics	Promoted beneficial oral bacteria; increased SCFA production; reduced pro‐inflammatory signaling	Preclinical + in vitro	Early investigation	(174)
Lung cancer	Probiotic mixtures	Modulated lung–gut immunity; reduced pro‐inflammatory signals	preclinical	Early experimental	(175–177)
	Postbiotics (EPS, SCFA derivatives)	Anti‐inflammatory; immune priming; reduced tumor progression	Preclinical	Very early stage	(123, 153, 178)
Cervical cancer	Probiotic/Synbiotic (Lactobacillus spp. + fiber)	HPV clearance; improved immune response; restored vaginal milieu	Observational + preclinical	Early investigation	(125, 179)
	Postbiotics (Lactic acid, biosurfactants)	Maintained vaginal pH; enhanced anti‐HPV immunity; reduced inflammation	Preclinical + pilot clinical In vitro	Experimental	(180–182)

Abbreviations: BCG: Bacillus Calmette‐Guérin; EPS: Exopolysaccharides; HPV: Human Papilloma Virus; SCFAs: Short‐chain fatty acids.

6. Current Challenges in Microbiome‐Based Cancer Prevention and Therapies

Despite growing evidence supporting the use of PPSPs in cancer prevention and treatment, significant obstacles remain. Biological complexity, including individual variations in diet, genetics, and microbiome composition, makes it difficult to generalize findings across different cancer types [123, 124]. The exact molecular mechanisms by which gut microbes influence cancer development and treatment responses remain unclear, limiting targeted therapeutic strategies [123]. Most existing research relies on animal models, particularly mice, which may not fully replicate human microbiome–host interactions. Translating these findings to human applications requires careful validation [125]. Additionally, strain‐specific effects where some probiotics suppress tumors while others may worsen inflammation highlight the need for precise formulation optimization [126, 127]. Clinical translation is further hindered by a lack of large‐scale human trials, standardized protocols, and safety concerns, particularly for immunocompromised patients. Addressing these challenges is critical for advancing microbiome‐based cancer therapies [127, 128].

7. Future Directions for Advancing Microbiome‐Based Cancer Therapies

To address existing challenges, future studies must prioritize precision microbiome medicine, utilizing cutting‐edge profiling technologies to customize therapies according to individual microbiome compositions, immune profiles, and cancer subtypes. Closing these knowledge gaps and fostering innovation will be critical (Figure 4). Mechanistic studies using multi‐omics approaches (metagenomics, metabolomics) will help identify key microbial metabolites and their roles in immune modulation and tumor suppression [129, 130]. Well‐designed clinical trials are essential to validate efficacy, establish dosing protocols, and assess long‐term safety, particularly in combination with existing therapies like immunotherapy. Bioengineering innovations, such as next‐generation probiotics and synthetic postbiotics, could enhance therapeutic precision and stability [131, 132]. Additionally, patient‐centered approaches, including biomarker development and cost‐effective manufacturing, will be crucial for clinical adoption. By addressing these challenges through interdisciplinary collaboration, microbiome‐based therapies could become a transformative component of cancer treatment in the future.

FIGURE 4.

An illustration highlighting the current challenges and future directions for advancing microbiome‐based cancer therapies.

8. Conclusion and Outlook

Emerging research unequivocally highlights the transformative potential of microbial therapeutics including probiotics, prebiotics, synbiotics, and postbiotics (PPSPs) to revolutionize cancer prevention and treatment. This review consolidates compelling evidence that these interventions act through multifaceted mechanisms, such as immune modulation, gut barrier enhancement, attenuation of chronic inflammation, and direct anti‐tumor effects, including apoptosis induction and angiogenesis suppression. Demonstrated efficacy across diverse malignancies, from colorectal and breast to gastric and hepatic cancers, positions PPSPs as powerful adjuvants that can enhance conventional therapy outcomes while reducing treatment‐related toxicities. Despite this promise, clinical translation is hindered by significant challenges rooted in biological individuality. Critical hurdles include strain‐specific optimization, interpatient microbiome variability, lack of standardized protocols, and the need for rigorous safety profiling, particularly in immunocompromised populations. The future of this field depends on a concerted, cross‐disciplinary effort focusing on key priorities. Progress will require the development of personalized microbiome‐targeting regimens, leveraging multi‐omics technologies to tailor interventions to an individual's unique microbial and immune profiles. Moreover, elucidating the dynamic crosstalk between microbial metabolites and oncogenic pathways using advanced models is essential to move beyond correlation toward causation. This foundational work must be supported by robust clinical validation through large‐scale trials to establish efficacy, optimize dosing, and confirm safety. Emerging innovations such as engineered designer probiotics and stabilized postbiotic derivatives, combined with conventional therapies, have the potential to pioneer novel combinatorial approaches. As mechanistic insights into the microbiome–cancer axis expand, microbial therapeutics are evolving from supportive adjuncts to cornerstone modalities in precision oncology. Achieving this paradigm shift will require sustained collaboration, strategic investment in translational pipelines, and adoption of a patient‐centered framework to effectively realize the vast potential of gut microbiome science in delivering safe, effective, and clinically actionable cancer interventions.

Author Contributions

All the authors actively contributed to the preparation of this manuscript. B.A.T., D.A., Z.H.T., A.F., and H.B. conceptualized and designed the study. B.A.T., M.B., M.J., M.G., T.B., W.Y.B., S.A.W., and T.K.Z. prepared the original draft. B.A.T., D.A., Z.H.T., A.F., H.B., M.B., M.J., M.G., T.B., F.B.T., W.Y.B., S.A.W., and T.K.Z. reviewed and edited the manuscript. All the authors read and approved the final manuscript.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Tegegne B. A., Abebaw D., Teffera Z. H., et al., “Microbial Therapeutics in Cancer: Translating Probiotics, Prebiotics, Synbiotics, and Postbiotics From Mechanistic Insights to Clinical Applications: A Topical Review,” The FASEB Journal 39, no. 20 (2025): e71146, 10.1096/fj.202502118R.

Data Availability Statement

Data will be made available on request.