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Abstract

Introduction

Immunotherapy approaches have improved by Immune check point inhibitors such as PD-1, CTLA-4, and PD-L1 inhibitors. However, the response to immunotherapy varies widely among patients due to various factors. Co-administration of probiotics with ICIs has become a promising strategy to improve therapeutic outcomes. This review evaluates the impact of environmental factors and life style on cancer pathophysiology, outcome of disease, and response to the treatment. It evaluates the role of probiotics in modulating immune responses and the synergistic interaction of probiotics with immunotherapy.

Methods

We conducted a comprehensive systematic review of clinical and preclinical studies to assess the effects of probiotics on immunotherapy outcomes. Studies were selected based on their focus on probiotics’ role in immune response modulation and interaction with ICIs. Data from trials involving patients with varying responses to immunotherapy, including those with prior resistance, were analyzed to explore the probiotic-enhanced immunotherapy.

Results

Gut microbiome has wide effects on immune responses through different pathways like production of short chain fatty acids (SCFAs), polysaccharide A, and indole-3-carbaldehyde. Also, probiotics found to enhance Anit-inflammatory responses and increase CD8+ T-cell activity, suggesting a synergistic effect with ICIs. Gut microbiota composition plays a key role in determining the effectiveness of immunotherapy, especially in treatment-resistant patients. For optimized treatment outcomes, personalized probiotics tailored to individual's microbiota showed potential. Important challenges are treatment resistance and compromised mucosal integrity because of microbiome alterations. Effective drug delivery also remains as important barriers to common adoption.

Conclusion

For immunotherapy outcomes improvement, immune responses modulation and gut microbiome diversity enhancement show probiotics important promise. Despite their potential, limitations must be addressed including treatment resistance and also delivery challenges. In order to maximize therapeutic benefits, personalized probiotic strategies have to be developed, and also the mechanisms by which probiotics improve ICI efficacy require elucidation through further research.

Keywords

immunotherapy immune checkpoint inhibitors (ICIs)probiotics microbiome personalized medicine SCFA polysaccharide A indole-3-carbaldehyde

Introduction

Effector T cells, particularly CD8+ T cells, play a crucial role in eliminating tumoral cells and controlling the development and progression of cancers by inhibiting tumor growth in both healthy individuals and cancer-bearing hosts.¹ Alongside CD8+ T cells, CD4+ T cells also have shown cytotoxic programs that directly attack cancer cells.² However, tumors deploy various immune inhibitory mechanisms to evade these antitumor responses, even in immune-competent hosts including immune suppressive molecules like Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4), Programmed cell death-1 (PD-1), and PD-ligand 1 (PD-L1).^1,3 Also, due to an imbalanced immune response, the highly activated phenotype of regulatory T cells in the tumor microenvironment causes tumor promotion.⁴

Immunotherapy enhances the immune responses against tumoral cells, without directly affecting target cancer cells.⁵ This innovative approach activates immune cells to recognize and attack malignant tissue. A significant area of research on immunotherapy revolves around immune checkpoint inhibitors including programmed cell death protein 1 (PD-1)/PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (See Table 1). These agents have shown potency in selectively targeting tumoral cells while sparing healthy cells.⁶

Table 1.

Overview of Drugs used for Immunotherapy.

Class	Drug	Cancer Type Treated	Adverse Side Effects
CTLA-4 inhibitors	Ipilimumab	Colorectal cancer,⁷ Esophageal carcinoma,⁸ Hepatocellular carcinoma,⁹ Malignant pleural mesothelioma,¹⁰ Melanoma,¹¹ Merkel cell carcinoma,¹² Non– small cell lung cancer,¹³ Renal cell cancer¹⁴	SJS,¹⁵ TEN,¹⁵ Type 1 DM,¹⁵ Cholangitis,¹⁵ Cholecystitis,¹⁵ Xerostomia,¹⁵ HLH,¹⁵ Neutropenia,¹⁵ Pure Red Cell,¹⁵ Sjogren disease,¹⁵ Myalgia,¹⁵ Dry eye syndrome,¹⁵ Pemphigoid,¹⁵ Hepatotoxicity,¹⁶
CTLA-4 inhibitors	Tremelimumab	Hepatocellularcarcinoma,¹⁷ Non– smallcelllungcancer¹⁸	Cardiac arrhythmia,¹⁹ Pericarditis,¹⁹ Myocarditis,²⁰ Myositis,²⁰ Vitiligo,²¹ Interstitial nephritis,²¹ Ocular toxicity¹⁸
PD-1 inhibitors	Nivolumab	Colorectal cancer,²² Esophageal cancer,²³ Hepatocellular carcinoma,⁹ Hodgkin lymphoma,²⁴ Malignant pleural mesothelioma,¹⁰ Melanoma,²⁵ Merkel cell carcinoma,¹² Non–small cell lung cancer,²⁶ Renal cell carcinoma,²⁷ Urothelial carcinoma²⁸	Acute kidney injury,¹⁵ Dry eye syndrome,¹⁵ Skin photo sensitivity,¹⁵ Graves disease,¹⁵ Cholecystitis,¹⁵ Esophagitis,¹⁵ Oral mucosal ulcer,¹⁵ ACS,²⁹ Acute aortitis,³⁰ Heart failure,³¹ Pericardial effusion,³² Pleural effusion,³² Bullous pemphigoid,³³ Lichen planus,³⁴ SJS,³⁵ TEN,³⁶ Ileitis,³⁷ Cholangitis,³⁸ Exacerbation of ulcerative colitis,³⁹ Sclerosing cholangitis,³⁸ Hemophilia,⁴⁰ DIC,⁴¹ AIHA,⁴² HLH,⁴³ Pancytopenia,⁴⁴ TTP,⁴⁵ TLS,⁴⁶ Aseptic meningitis,⁴⁷ Myasthenia gravis,⁴⁸ Discoid Lupus Erythematous,⁴⁹ Myalgia,⁵⁰ Systemic Sclerosis,⁵⁰ Lambert-Eaton syndrome,⁵⁰ Pulmonary hypertension,⁵⁰ Bilateral sensorineural hearing loss⁵¹
	Pembrolizumab	Biliary tract cancer,⁵² Breast cancer,⁵³ Cervical cancer,⁵⁴ Colorectal cancer,⁵⁵ Cutaneous squamous cell carcinoma,⁵⁶ Endometrial carcinoma,⁵⁷ Gastric cancer,⁵⁸ Hepatocellular carcinoma,⁵⁹ Hodgkin lymphoma,⁶⁰ Malignant pleural mesothelioma,⁶¹ Melanoma,⁶² Merkel cell carcinoma,⁶³ Mycosis fungoides [Sezary syndrome],⁶⁴ Non–small cell lung cancer,⁶⁵ Renal cell carcinoma,⁶⁶ Urothelial cancer⁶⁷	Capillary Leak syndrome,⁶⁸ Bullous pemphigoid,^15,69 Lichen planus,^15,70 Psoriasis,⁷¹ Pyoderma gangrenosum,⁷² TEN,⁷³ SJS,⁷⁴ Non-bacterial Cystitis,⁷⁵ Cytomegalovirus associated infections,⁷⁶ Tuberculosis reactivation,⁷⁷ Interstitial nephritis,⁷⁸ IgA nephropathy,⁷⁹ Necrotizing glomerulonephritis,⁸⁰ Aseptic meningitis,⁸¹ Demyelinating polyneuropathy,⁸² Neuromyelitis Optica,⁸³ Osteonecrosis of the jaw,⁸⁴ Cutaneous Lupus erythematosus,⁸⁵ Seronegative synovitis,⁸⁶ Dermatomyositis⁸⁷, TTP,⁸⁸ DIC,⁸⁹ Pancytopenia,⁹⁰ Agranulocytosis,⁹¹ Optic neuropathy,⁹² Retinal detachment,⁹³ Vision loss,⁹⁴ Exudative maculopathy,⁹⁵ Cholangitis,⁹⁶ Sclerosing cholangitis⁹⁷
	Cemiplimab	Cervical cancer,⁹⁸ Cutaneous squamous cell carcinoma,⁹⁹ Non– small cell lung cancer¹⁰⁰	Pemphigoid,¹⁵ TEN,¹⁵ SJS,¹⁵ Cholecystitis,¹⁵ Cholangitis,¹⁵ Esophagitis,¹⁵ Myalgia,¹⁵ Sjogren disease,¹⁵ Dry eye syndrome,¹⁵ Neutropenia,¹⁵ Pure Red Cell Aplasia,¹⁵ Hepatotoxicity¹⁶
PD-L1 inhibitors	Atezolizumab	Alveolar soft part sarcoma,¹⁰¹ Cervical cancer,¹⁰² Hepatocellular carcinoma,¹⁰³ Melanoma,¹⁰⁴ Non–small cell lung cancer,¹⁰⁵ Small cell lung cancer¹⁰⁶	Cholecystitis,¹⁵ Cholangitis,¹⁵ Esophagitis,¹⁵ Xerostomia,¹⁵ Neutropenia,¹⁵ Pure Red Cell Aplasia,¹⁵ Dry eye syndrome,¹⁵ Sjogren disease,¹⁵ Acute kidney injury,¹⁵ Cardiac tamponade,¹⁵ Pericardial effusion,¹⁵ Hepatotoxicity¹⁶
	Avelumab	Gestational trophoblastic neoplasia,¹⁰⁷ Merkel cell carcinoma,¹⁰⁸ Renal cell carcinoma,¹⁰⁹ Urothelial carcinoma¹¹⁰	Pemphigoid,¹⁵ SJS,¹⁵ TEN,¹⁵ Hypophysitis,¹⁵ Cholecystitis,¹⁵ Cholangitis,¹⁵ Esophagitis,¹⁵ Xerostomia,¹⁵ Pure Red Cell Aplasia,¹⁵ Sjogren disease,¹⁵ Myalgia,¹⁵ Dry eye syndrome,¹⁵ Uveitis,¹⁵ Hepatotoxicity¹⁶
	Durvalumab	Hepatocellular carcinoma,¹⁷ Non- small cell Lung Cancer,¹¹¹ biliary tract cancer,¹¹² Endometrial cancer¹¹³	SJS,¹⁵ TEN,¹⁵ Cholangitis,¹⁵ Cholecystitis,¹⁵ Neutropenia,¹⁵ Pure Red Cell Aplasia,¹⁵ Arthralgia,¹⁵ Arthritis,¹⁵ Myalgia,¹⁵ Dry eye syndrome,¹⁵ Sjogren disease,¹⁵ Hepatotoxicity,¹⁶ Myocarditis,¹¹⁴ Pericarditis,¹¹⁵ Hepatitis,¹¹⁵ Vasculitis,¹¹⁶ DKA,¹¹⁷ Type 1 DM,¹¹¹ Hyperthyroidism¹¹¹, Sarcoidosis,¹¹¹ Dyspnea,¹¹¹ Constipation,¹¹¹ Acute kidney injury,¹¹⁸ Diarrhea,^118,119 Gastritis,¹²⁰ Encephalitis,¹²¹ Esophagitis,¹¹⁹ Gastrointestinal hemorrhage,¹¹⁹ Nausea,^15,119 Vomiting¹¹⁹

The significance of immunotherapy is due to its high specificity and potency for long-term effectiveness; however, its applicability is not universal since the outcomes vary significantly across different types of cancer and patients.¹²² This variability emphasizes the necessity for future explorations and innovations to seek optimal treatment strategies.

CTLA-4, an immune checkpoint inhibitor molecule, is critical in regulating T-cell responses. While the basal expression level of this molecule is low, it can be strongly upregulated following antigen-mediated activation.¹²³ As a consequence of this upregulation, activation and proliferation of T-cells are reduced by disruption of CD28-B7 interaction and suppression of T-cell receptor signaling pathway.¹²⁴ Also, it has been shown that blocking this molecule with neutralizing antibodies can enhance antitumor immunity in mice.^123,125 PD-1 is another immune checkpoint molecule that causes negative regulation of T-cell activation.¹²⁶ Its significance became evident in 1999 when the loss of PD-1 in mice led to autoimmune conditions, highlighting its role in maintaining immune tolerance. Engagement of PD-1 with its ligands like PD-L1 causes T-cell exhaustion, a dysfunction that impairs the immune response.¹²⁷ PD-L1 is also expressed in antigen-presenting cells which regulates the differentiation and suppressive function of regulatory T-cells (Treg).¹²⁸ By increasing PD-L1 expression, tumor cells take advantage of this pathway and lead T-cells to exhaustion, which fosters a tumor microenvironment conducive to tumoral growth and invasion.¹²⁹ (See Figure 1.)

Figure 1.

Molecular Mechanisms of Immunotherapy in Cancer. Interaction of PD-1/PD-L1 and CTLA-4 Pathways with T cells is Depicted.^130–134

Building upon the role of immune modulation in cancer therapy, probiotics—live microorganisms that confer health benefits—are a promising tool to improve antitumor responses by shaping the gut microbiome. These are helpful microorganisms that are generally recognized as safe (GRAS). However, fully understanding their therapeutic use requires more studies to fill the knowledge gaps. A comprehensive review highlighted that while probiotics influence lipid profiles and gut microbiome composition, their effects are often inconsistent and transient.¹³⁵

Probiotics act as an active modulator of the gut microbiome and the immune system by increasing short-chain fatty acid (SCFA)-producing bacteria (critical metabolic byproducts that significantly impact immune function), controlling pathogenic bacteria via producing antimicrobial peptides, bacteriocins, and butyrate, and also altering gut environmental factors such as pH which induces cancer cell apoptosis.⁶ Additionally, they improve gut permeability by promoting mucus secretion, enhancing gut barrier functions, and preventing pathogen adhesion.^6,136

Next-generation probiotics including human commensal species such as Faecalibacterium prausnitzii and Akkermansia muciniphila can prevent cancer as well as obesity and inflammatory bowel disease.^137,138 F. prausnitzii regulates the host's immune system by producing polysaccharide A, which can result in immune response enhancement and CD8+ T cell activation.⁶

In cancer patients, conventional treatments such as chemotherapy, radiotherapy, and surgery can create unfavorable conditions for the colonization of probiotics, particularly in individuals with colorectal cancer.¹³⁹ As the potential effects of probiotics are related to the gut microbiome composition, it can be concluded that both probiotics and gut microbiome can affect the outcome of immunotherapy.^139,140 Probiotics also take part in competition for nutrients in the distal colon, regulating natural killer (NK) cell activity, and inhibiting the growth of pathogenic gram-negative bacteria. They also reduce the activity of bacterial enzymes responsible for producing carcinogenic compounds by creating an acidic environment.^141,142

Molecular pathological epidemiology (MPE), a new field of epidemiology which is a multidisciplinary assessment of relations between tumoral features including tumor markers, progression, and other factors such as genetic, environment, lifestyle, and epidemiology by integrating epidemiology and molecular pathology methods.¹⁴³ This approach leads to identification of specific patterns in tumors to expand targeted treatments and individualized medicine.¹⁴⁴ Also, a widespread field of MPE is investigation of gut microbiome and its relationship between epidemiological factors and tumoral factors like modulation of immune response, alteration of tumor microenvironment, and response to treatment.¹⁴⁵

Previous studies have evaluated the role of gut microbiome in enhancement of cancer immunotherapy outcomes. Lu and colleagues analyzed the modulation of immune system by microbiome.¹⁴⁶ Also, Jiang and colleagues emphasized the increase of immunotherapy effectiveness by probiotics.⁶ Kang and colleagues proposed a microbe-based strategy for enhancement of anti-tumor treatment.¹⁴⁷ However, in this review, we have studied the precise mechanism of immune checkpoint inhibitors, interaction of immunotherapy and microbiome, and also we have discussed MPE and its potential role in improvement of personalized medicine. Challenges and limitations ahead in using the microbiome to improve cancer treatment outcomes and future directions have also been discussed.

Methods and Materials

Our review article employs a systematic approach to gather, analyze, and synthesize existing literature regarding the integration of probiotics into cancer therapy, particularly focusing on their effects on patients undergoing immunotherapy.

This systematic review was conducted in accordance with the PRISMA guidelines¹⁴⁸ and is registered in the INPLASY database (Registration number: INPLASY202570044).

Literature Search Strategy

A comprehensive literature search was conducted using several reputable academic databases, including PubMed, Scopus, Web of Science, science direct, and Google Scholar. Keywords and phrases covering “probiotics”, “cancer therapy”, “immunotherapy”, “microbiome”, “immune checkpoint inhibitors (ICIs)”, “personalized medicine”, “SCFA”, “polysaccharide A”, “indole-3-carbaldehyde”, “molecular pathological epidemiology”, “environmental factor”, and “lifestyle” were used to identify relevant articles. Boolean operators (AND, OR) were applied to refine search results. Additionally, the references of relevant articles were reviewed to find more related studies as well as papers that cited our selected references to ensure we covered all important literature. The search was conducted to capture the most relevant and recent advancements in the field. No restrictions on study type or geographical scope were applied. Also, the search was included publications from 1995 to 2024, capturing the most relevant and recent advancements in the field.

Inclusion and Exclusion Criteria

Inclusion Criteria: Studies were considered for inclusion if they:

Focused on the use of probiotics in cancer treatment.

Explored the microbiome's role in modulating immune responses during cancer therapies.

Provided clinical data, case studies, or insights on the safety and efficacy of probiotics.

Explained the role of SCFA, polysaccharide A, and indole-3-carbaldehyde in regulating immune system.

Discussed molecular pathological epidemiology, environmental factors, and lifestyle and their relation to cancer and its treatment.

Were peer-reviewed articles, clinical trials, meta-analyses, or systematic reviews.

Exclusion Criteria: Articles were excluded if they:

Were not available in English.

Had no full-text available.

Had unclear methodology or reporting.

Focused on topics unrelated to cancer therapy or probiotics.

Data Extraction and Analysis

After collecting resources, duplications were removed manually and were evaluated for risk of bias by assessing key methodological aspects including randomization, blinding, sample size, completeness of outcome data, selective reporting, and reviewing the conflict-of-interest statement. A two-phase screening process was performed: First, the abstract of articles was reviewed, and then the full text of all articles was examined by five independent authors to extract key information from each selected article including details on study design, patient demographics, types of probiotics administered, treatment protocols, outcomes measured, and key findings related to the effectiveness of probiotics in cancer therapy. The findings were categorized based on themes such as the impact of probiotics on therapeutic application, treatment side effects, immune modulation, microbiome diversity, and overall patient outcomes. Three authors retrieved the studies and any disagreements were resolved by two authors. A narrative synthesis was conducted to present a cohesive understanding of how probiotics can be integrated into cancer treatment and future roadmap.

Ethical Considerations

This study is a systematic review that analyzes existing published. Since no new data were collected from humans, animals, or biological samples, and only previously published studies with their own ethical approvals were used, this review does not require separate ethical approval.

Environment and Lifestyle Role in Cancer Pathophysiology

Environmental factors and lifestyle play a role in cancer development and progression through various molecular mechanisms. Exposure to carcinogenic chemicals such as benzene (present in cigarette smoke and industrial emissions) can lead to mutations in key genes involved in regulation of cell cycle and DNA repair like TP53, resulting in cancers like leukemia.¹⁴⁹ UV radiation from the sun causes direct damage to DNA, leading to mutations like BRAF, which is common in melanoma.¹⁵⁰ Poor diet, such as eating too many processed or low-fiber foods, can increase the risk of colorectal cancers by increasing chronic inflammation in the intestine, particularly by activation of the NF-κB signaling pathway.¹⁵¹ Low exercise is associated with increased levels of insulin-like growth hormone (IGF-1), which results in stimulation of abnormal cell proliferation, as in breast, colon, and endometrial cancer.¹⁵² Also, by increasing cortisol production, chronic psychological stress suppresses the immune response and leads to tumor progression, particularly by reducing the activity of natural killer cells (NK cells).¹⁵³ Exposure to heavy metals like arsenic in water increases the risk of lung, bladder, and kidney cancer by induction of oxidative stress and disruption of DNA repair pathways.^154,155 Individual differences in exposure to environmental and lifestyle factors influence disease outcomes and response to treatment. Long-term exposure to asbestos causes chronic lung inflammation and DNA damage, which increases the risk of mesothelioma.¹⁵⁶ Alcohol consumption impairs the efficacy of anticancer drugs such as tamoxifen in the treatment of breast cancer by increasing estrogen levels and disrupting hormonal metabolism, particularly in patients with weak CYP2D6 genotypes that limit the capacity to produce the active metabolite of endoxifen.^157,158 Smoking-induced EGFR activation leads to resistance against EGFR inhibitors in lung cancer through sustained survival signaling.¹⁵⁹ Genetic polymorphisms in the GSTM1 gene alter susceptibility to carcinogens such as cigarette smoke and affect response to treatment.¹⁶⁰

Molecular Pathological Epidemiology

Molecular Pathological Epidemiology is a new interdisciplinary field that aims to gain a better understanding of the interaction between genetic and environmental factors in the initiation, progression, and response to treatment in cancer.¹⁶¹ Unlike traditional epidemiology, which analyzed the disease as a uniform entity, MPE seeks molecular differences between various cancers, which results in diversity in response to treatment. Recent studies revealed that there is an association between lifestyle and tumor type. For instance, consumption of processed meat is associated with colorectal cancer in which Fusobacterium nucleatum is abundant. This bacterium can modulate the immune response against tumors.¹⁶² Similarly, aspirin use is more strongly associated with improved survival in colorectal cancers with PIK3CA mutations, but not in wild-type tumors.¹⁶³ These results show that paying attention to the molecular differences of tumors can help in more accurate selection of treatment and even prevention.

MPE could also be useful in the field of immunotherapy. For example, it has been shown that factors such as the composition of the gut microbiome, obesity, or alcohol consumption can alter the structure of the immune system in TME and affect the response to treatment.¹⁶² A recent study demonstrated that abundant dietary fiber can improve the response to anti-PD-1 treatment in melanoma, particularly in patients with high diversity of gut microbiome and SCFA-producing bacteria.¹⁶⁴ These complicated interactions would not be evident without classification by molecular or microbial subtypes, which is the core principle of MPE. MPE is gradually finding applications in the clinic. For example, it is used to identify biomarkers and select more appropriate treatments.¹⁶² As a result, adding MPE to future studies can reveal new sides of this type of epidemiology to improve the efficacy of individualized medicine. Molecular pathological epidemiology (MPE) helps researchers understand how lifestyle, environment, and molecular features of a disease are connected. This information can be used to group patients more accurately and choose better treatments based on their individual characteristics. Instead of giving the same treatment to everyone, MPE allows doctors to adjust the plan to each person.

Probiotics and Microbiome in Immunotherapy

Emerging evidence suggests that the composition of the gut microbiota significantly affects the efficacy of cancer immunotherapies, particularly immune checkpoint inhibitors (ICIs). Also, it appears to affect outcomes of chimeric antigen receptor T cell therapies.¹³⁵ Fecal microbiota transplantation (FMT), when combined with ICIs, has shown potency in changing the tumor microenvironment and boosting host immunity in different malignancies such as melanoma,¹⁶⁵ prostate, and gastrointestinal cancers.¹³⁵ Moreover, a disrupted gut microbiome can cause immunity dysfunction, which suppresses immune responses. The microbiome thus plays a critical role in regulating these responses, particularly affecting the effectiveness and side effects of ICIs.⁶ Besides this, combining probiotics (such as Lactobacillus rhamnosus and Bifidobacterium lactis) with prebiotics could inhibit cancer progression, particularly colon cancer.¹⁶⁶ Prebiotics can help restore microbial diversity, promoting beneficial microbes and potentially enhancing treatment outcomes.¹⁶⁷

The interactions between cancer and the gut microbiome are not that simple. Gut bacteria metabolize dietary compounds that may affect tumor development and progression; although they can also produce metabolites that contribute to cancer progression, particularly colorectal cancers;¹⁶⁸ For example, certain pathogens such as Helicobacter pylori and E. coli, are associated with gastric¹⁶⁹ and colorectal cancers,¹⁷⁰ respectively. Similarly, β-glucuronidase enzyme, which is secreted by the gut microbiome, can promote the risk of estrogen-dependent malignancies such as breast, ovarian, and endometrial cancers by converting estrogen into its free form.¹⁷¹ These examples show how the gut microbiome can turn harmful, particularly as its composition disrupts. Also, interventions such as antibiotics, probiotics, and prebiotics sometimes lead to dysbiosis, which complicates the treatment.¹⁴¹ Dysbiosis also affects the outcomes of radiation therapy, which highlights the role of the microbiome in cancer treatment.¹⁷²

Given these impacts, maintaining a balanced microbial composition in patients is crucial for optimizing therapeutic success, as disruptions can impair immune recovery and negatively affect both the efficacy of treatments and the occurrence of side effects.¹⁷³

The gut microbiome varies by individual due to genetics, diet, environment, medications, and lifestyle (eg, smoking), affecting its role in cancer immunotherapy,^174–176 which acts as a biomarker that can predict the response to the treatment. For instance, patients with high levels of Faecalibacterium show a high presence of immune cells in the TME, indicating that specific gut microbiome can enhance anti-tumor immunity.¹⁴¹ According to these, manipulating the gut microbiome can be an effective strategy to enhance the efficacy of immunotherapy. Two strategies can be utilized to achieve this goal: introduction of beneficial microbial populations to restore diversity of microbiome and enhance immune response to facilitate effective anti-tumor activity;¹⁷⁷ and targeting the harmful microbial population which impair immune system function, disrupt microbial balance, and promote tumor growth.^178,179 SCFAs, which are produced via fermentation of dietary fibers by gut bacteria, have a crucial role in maintaining health, as reduction in SCFAs level is often associated with inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), type 2 diabetes, obesity, and cancer.¹⁸⁰ These SCFAs significantly regulate the immune system in complex pathways; exhibiting a dual role in murine models, as they support certain immune functions, they also may limit the efficacy of anti-CTLA-4 therapy by restriction of molecular expression in immune cells.¹⁸¹ However, as an anti-inflammatory and anti-carcinogenic agent, they act through various mechanisms such as inhibiting histone deacetylase (HDAC) activity and acting as a ligand for G-protein-coupled receptor to facilitate the expansion and differentiation of regulatory T-cells and promote immunosuppressive cytokines production¹⁸² (see Figure 2). As previously mentioned, the connections between the gut microbiome, SCFAs, and immune modulation highlight the potential for targeted microbiome manipulation to enhance immunotherapy outcomes in cancer treatment, which offers valuable avenues for therapeutic advancements.¹⁸³

Figure 2.

Role of the Gut Microbiome in Immune Modulation for Cancer Immunotherapy. The gut Microbiome Produces Metabolites such as SCFAs (Including Butyrate, Propionate, and Acetate), Polysaccharide A, and Indole-3-Carbaldehyde. These Metabolites Modulate Immune Responses by Interacting with G Protein-Coupled Receptors (GPCRs) (Including GPR43, GPR109A), Histone Deacetylase (HDAC), PPARγ, Toll-like Receptor 2 (TLR2), and Aryl Hydrocarbon Receptor (AhR) Pathways, Promoting IL-10 Production to Reduce Inflammation (TNF-α, IL-6), Enhancing IFN-γ and IL-12 Secretion, and also Boosting Anti-Tumor Immunity by Th1, CD8+ T cells, and NK Cells. This Modulation Improves the Tumor Pmicroenvironment, Enhancing the Efficacy of Immune Checkpoint Inhibitors.^6,182–196

Polysaccharide A, which is mainly produced by Bacteroides fragilis in the gut microbiome, has an important role in regulation of the immune system.¹⁸⁴ By activation of Toll-like receptor 2 (TLR-2), PSA stimulates the production of anti-inflammatory cytokines such as IL-10 and shifts the balance between inflammatory T-cells (Th1/Th17) and regulatory T-cells in favor of anti-inflammatory response.¹⁸⁵ This potency of PSA results in reduction of chronic inflammation due to cancer.¹⁸⁶ Furthermore, studies have shown that PSA can modulate the tumor microenvironment and improve the response to cancer immunotherapies, such as immune checkpoint inhibitors.¹⁸⁷ These effects occur through enhancing immune cell activity and reducing immunosuppression in the tumor microenvironment.¹⁸⁸ Therefore, PSA, as a key microbial metabolite, has great potential for the development of novel therapeutic strategies in cancer immunotherapy¹⁴⁵ (see Figure 2).

Indole-3-carbaldehyde, another microbiome-generated metabolite through tryptophan metabolism by bacteria such as Lactobacillus, acts as a ligand for aryl hydrocarbon receptor (AhR).¹⁹⁷ The activation of AhR enhances the anti-inflammatory response and increases IL-22 production that decreases the chronic inflammation related to cancer.¹⁸⁹ Furthermore, indole-3-carbaldehyde can improve the response to immunotherapy like immune checkpoint inhibitors by modulating the tumor microenvironment.¹⁹⁰ These findings show that targeted manipulation of the gut microbiome to increase the production of metabolites such as SCFAs, PSA, and indole-3-carbaldehyde can be a strategy to enhance the outcomes of immunotherapy¹⁴⁶ (see Figure 2).

Probiotics can elevate SCFA production and anti-inflammatory cytokines (eg, IL-10) while reducing inflammation markers (eg, CRP, TNFα).^191,192 Specific bacteria, such as Roseburia species, are critical for butyrate production, influencing the activation of peroxisome proliferator-activated receptors (PPARs).¹⁹³ Activation of PPARs, especially PPARγ, is crucial for modulating immune responses and achieving anti-inflammatory effects. Probiotics such as Lactobacillus casei Zhang can increase butyrate production, which results in activation of PPARγ and inhibition of NF-κB pathway, eventually reducing inflammation.¹⁹⁴ Similarly, Lactobacillus reuteri DSM 17938 supports PPAR signaling pathways, leading to reduced inflammation and promotion of cancer cell apoptosis through an undefined mechanism.¹⁹⁵ Also, Lacticaseibacillus casei promotes propionic acid fermentation, which enhances PPARγ activity and inhibits pro-inflammatory TLR-4 signaling.¹⁹⁶ Different PPAR isotypes can either suppress or promote cancer, based on various factors like isotype type, cancer type, and tumor stage:^198,199

PPARα: Inhibits cancer progression by reducing angiogenesis.

PPARγ: Can inhibit proliferation and metastasis but may also support tumor growth under certain conditions.

PPARβ/δ: Exhibits diverse effects, potentially promoting tumorigenesis while influencing the energy metabolism of tumor cells.

Clinical Evidence: Microbiome in Cancer Immunotherapy

As previously described, modulation of gut microbiota through probiotics has gained attention as a promising strategy to enhance the efficacy of cancer immunotherapy, especially immune checkpoint inhibitors (ICIs). Evidence suggests that increasing bacterial diversity through probiotics or fecal microbiota transplant (FMT) can address resistance to tumor immunotherapy.^200–202

Tanoue and colleagues isolated 11 bacterial strains from healthy donors that could stimulate CD103 + dendritic cells to induce IFNγ-producing CD8+ T cells. This activation enhanced the effectiveness of anti-PD-1 therapy in mouse models of MC38 adenocarcinoma.²⁰³

Le Noci and colleagues showed that aerosolized Lactobacillus rhamnosus boosted immunity against lung metastases and enhanced the response to chemotherapy in mice.²⁰⁴

Guangqi Gao and colleagues reported that supplementation with Lactobacillus pentosus increased beneficial metabolites, which improved the response to anti-PD-1 therapy and raised blood levels of metabolites such as α-ketoglutarate.²⁰⁵

In studies on melanoma, Mackenzie J. Bender and colleagues found that Lactobacillus reuteri produced indole-3-carbaldehyde (I3A), which activates the aryl hydrocarbon receptor (AhR) and boosted interferon-gamma production, thereby enhancing immune checkpoint inhibitor (ICI) therapy.¹⁹⁰

Routy et al demonstrated that Akkermansia muciniphila is a mediator, linking immunotherapy and treatment responses in mice with MCA-205 sarcoma and RET melanoma. Also, following non-responders to immune checkpoint inhibitors (ICI), oral administration of A. muciniphila restored the effectiveness of PD-1 blockade through an IL-12 dependent process, which facilitated the recruitment of CCR9 + CXCR3 + CD4+ T lymphocytes into epithelial tumors.²⁰⁶

Iida N. and colleagues showed that the gavage of Alistipes shahii in antibiotic-treated mice restored immunotherapeutic responses, highlighting the critical role of the microbiome in treatment efficacy.²⁰⁷

Fecal microbiota transplantation (FMT) from long-term anti-PD-1 responders into PD-1-resistant melanoma patients showed improved response. While variations in donor profiles and administration methods were noted, all studies linked FMT to enhanced efficacy of PD-1 therapy.^165,208

An imbalance between Bacteroidetes and Firmicutes species negatively impacted responses to PD-1 targeted therapies.²⁰⁹ Davar et al found that probiotics containing live bacteria significantly improved outcomes in refractory cancer patients when used alongside immune checkpoint inhibitors (ICIs).²¹⁰

Ongoing trials are evaluating various microbial ecosystems with anti-PD-1 therapy. For instance, Clostridium butyricum (CBM588) has shown promising results and increased response rates in patients with advanced renal cell carcinoma.²¹¹

As elaborated above, numerous studies have shown that specific probiotic strains can significantly improve the efficacy of immune checkpoint inhibitors (ICIs). These studies suggest that probiotics may promote the activation and proliferation of CD8+ T cells, which are essential for initiating and sustaining anti-tumor immunity. Additionally, probiotics can stimulate pro-inflammatory responses, potentially creating a synergistic effect when combined with conventional cancer therapies. This synergy is significant in overcoming the immune evasion strategies employed by tumors, thereby leading to improved patient outcomes.²¹² Clinical trials, including those involving FMT from long-term responders to ICIs,^165,208 provide compelling evidence of the importance of gut microbiota in determining therapeutic efficacy. The interventions on gut microbiome to restore its diversity have demonstrated the potency to shift the immune landscape toward an improved anti-tumor response, as in patients with prior resistance to PD-1 therapies. These findings highlight the role of gut microbiome in modulation of the immune system and emphasize the importance of future studies on microbial composition in therapeutic strategies. The success of these trials also demonstrates the potency of microbiome-based therapies as an adjuvant to conventional cancer treatments. However, there are several challenges and limitations in employing these findings in clinical practice, as discussed in the following section.

Challenges and Limitations

Challenges

Resistance and Treatment-Related Toxicities

Integrating probiotics into cancer treatment faces challenges, particularly regarding treatment resistance, which complicates efforts to achieve sustained benefits from immunotherapy. Additionally, reported adverse effects, such as gastrointestinal inflammation,²¹³ raise concerns about the safety of probiotic applications in sensitive cancer patient populations.

Impaired Mucosal Barriers

Compromised mucosal integrity in many cancer patients can impede the effective colonization and functioning of probiotics.¹³⁹ Tumors can alter the local environment, affecting microbiome diversity and stability,²¹⁴ which may limit the beneficial effects of probiotic therapies.

Real-Time Monitoring

Lack of precise measurement tools to evaluate the change of microbiome after probiotic administration in patients causes a question for physicians to show whether the treatment with probiotics was effective or not.

Delivery Mechanisms

Effective delivery and stability of probiotics present additional hurdles. The gastrointestinal tract is a hostile environment, and many probiotics may lose viability before reaching their intended targets.

Optimal Dosage and Timing

The appropriate dose of probiotics, along with the timing and sequence of their administration—particularly how long before starting conventional cancer treatments—remains unclear and poses a significant challenge ahead.

Limitations

Variability in Microbial Responses

The variability in microbial responses among individual patients complicates the application of probiotics in immunotherapy. Personal differences in microbiome composition can significantly influence the effectiveness of administered probiotics, making a one-size-fits-all approach ineffective. As mentioned, factors such as genetics, diet, previous antibiotic use, and lifestyle play substantial roles in shaping individual microbiomes,^174–176 necessitating a nuanced understanding to guide interventions.

Lack of Comprehensive Understanding

Despite significant advancements in medicine, the mechanisms of immune modulation and enhancement of clinical responses to immunotherapy by probiotics are still partially understood.

Limited Human Studies

While preclinical data are promising, a basic limitation is the lack of clinical studies to evaluate the safety and efficacy of probiotics in various cancers. Current studies often vary in approach and methodology, which results in inconsistency of findings.

Future Directions and Conclusion

Addressing Resistance and Toxicity and Delivery in Probiotic use

As previously described, despite the effectiveness of ICIs, resistance and treatment-related toxicities, like intestinal inflammation, remain significant challenges. Yet, the modulation of gut microbiota through probiotics has gained attention as a promising strategy to enhance efficacy and address resistance. Targeted probiotics, such as B. longum, could mitigate inflammation without compromising antitumor effects.²¹⁵ Also, emphasizing optimized delivery pathways is crucial. Innovative delivery mechanisms, such as protective coatings or encapsulation technologies,²¹⁶ are being explored to enhance the stability and bioavailability of probiotics. However, these solutions must be carefully optimized to ensure they do not compromise the inherent activity or therapeutic benefits of the probiotics.

Tailoring Probiotic Treatment for Different Patients

The growing field of microbiome research has opened up new avenues for personalized medicine, particularly in the integration of probiotics to immunotherapy. In comparison to employing a one-size-fits-all approach, tailoring probiotics to individual patients enhances therapeutic outcomes significantly. Identification of specific bacterial strains which are capable to modulate immune responses introduces exciting opportunities for enhancing immunotherapy and advancing personalized medicine. Researchers can tailor probiotic therapies to maximize the outcome of treatment by analyzing the microbiome profiles of different patients with appropriate response to treatment alongside the individual patient's microbiome. Personalized approaches may include selecting specific probiotic strains based on a patient's microbial flora, genetic predispositions, previous treatment experiences, and also molecular pathological epidemiology. This customization ensures that therapies could be more effective while adverse effects are minimized, leading to better patient adherence and outcomes. Below are critical considerations that highlight the importance of personalization in probiotic treatments:

Individual Microbiome Profiles: Recent studies have demonstrated that each individual possesses a unique microbiome composition that influences their immune response and therapy treatment effectiveness.²¹⁷ This variability underscores the necessity of personalized approaches where probiotics can be selected to suit an individual's specific microbial composition.

Genetic and Environmental Influences: Genetics, diet, and lifestyle can profoundly affect an individual's gut microbiota. A study by Zmora et al suggests that dietary patterns directly influence microbial diversity and function, which can modulate immune responses.¹⁴⁰ Incorporating dietary assessments into the personalization of probiotic treatments could optimize efficacy. For instance, patients following a high-fiber diet can benefit from fiber-fermenting probiotics, while others may require different strains based on their dietary intake.

Targeting Specific Patient Populations: Certain cancer types may respond better to specific probiotic interventions. For example, Akkermansia muciniphila has been shown to enhance immunity and improve checkpoint inhibitor responses, particularly in colorectal cancer patients.²⁰⁶ Understanding the specific needs of different tumor types will help to guide the selection of probiotics that can specifically enhance immune responses relevant to particular cancers.

Factors Influencing Probiotic Effectiveness: The effectiveness of probiotics can be influenced by several patient-related factors such as age, underlying health conditions, and concurrent treatments. A systematic review highlighted that older adults often experience reduced gut microbiome diversity, which affects probiotic outcomes.²¹⁸ Thus, geriatric patients may require higher doses or more potent strains of probiotics to achieve the desired therapeutic effects.

Integration of Probiotics with Other Treatments: Personalized probiotic treatments can also be designed to complement existing therapies. For example, the administration of probiotics alongside standard chemotherapy regimens could mitigate adverse effects like diarrhea and mucositis.²¹⁹ This integrated approach necessitates an understanding of both the cancer treatment protocols and the specific probiotic strains that can provide synergistic effects.

Clinical Trials and Biomarkers: Ongoing clinical trials are essential to identifying effective probiotic strains for specific patient groups. Studies like those by Davar et al²¹⁰ aim to correlate changes in the gut microbiome with treatment responses, providing valuable data to refine probiotic formulations. The discovery of biomarkers that predict responses to specific probiotics will be instrumental in tailoring treatments effectively.

Ethnic and Geographic Variability: A study²²⁰ demonstrated that ethnic and geographic factors could influence the efficacy of probiotics in promoting gut health. Therefore, developing region-specific probiotic formulations that consider local diets and cultural practices may enhance therapeutic success.

Personalized Communication Strategies: Effective communication between healthcare providers and patients about the role of the microbiome in cancer therapy is crucial. Providing education and resources about how probiotics can be personalized based on individual microbiomes and health profiles can empower patients. Tailored recommendations based on personal and familial health histories will also help patients make informed choices about their probiotic use during treatment.

Integrating Probiotics into Cancer Therapy: A Future Roadmap

The integration of probiotics into cancer therapy represents a paradigm shift in how we approach accessible treatment modalities. The fact that personalized probiotic therapies can enhance treatment outcomes in cancer patients is getting clearer as our understanding of the microbiome and its interaction with the immune system deepens. The path forward involves several strategic approaches, which can be outlined as follows:

Personalized Probiotic Formulations: Future research should focus on developing personalized probiotics tailored to individual microbiome profiles. Advances in metagenomics and metabolomics will facilitate the identification of specific bacterial strains that can augment the efficacy of conventional therapies based on patient-specific biomarkers.

Clinical Protocols: Establishing standardized protocols for the administration of probiotics alongside cancer treatments is crucial. Clinical trials should aim to determine optimal strains, dosing regimens, and timing of probiotic administration relative to cancer therapies. This structured approach will provide scientific evidence to support probiotic use in oncological settings.

Monitoring and Assessment: Regular monitoring of gut microbiome composition and patient outcomes should be integrated into clinical practice to assess the impact of probiotics. Biomarkers that indicate microbiome health and treatment efficacy (eg, levels of specific metabolites or immune response markers) will help make clinical decisions and allow for real-time adjustments to probiotic therapies.

Addressing Safety and Efficacy: Comprehensive safety evaluations are critical when integrating probiotics into cancer therapy. Understanding potential risks, especially in immunocompromised patients, will lead to more informed decisions regarding the use of specific probiotic strains.

Educational Initiatives: Education for healthcare providers and patients about the potential benefits and limitations of probiotics in cancer therapy will be essential. Clinicians should be equipped to discuss how probiotics may complement traditional therapies and address associated concerns, fostering a collaborative treatment approach.

Interdisciplinary Research Teams: To fully harness the potential of probiotics in cancer therapy, collaborative efforts between oncology, microbiology, immunology, and nutrition experts are necessary. Such interdisciplinary research teams can explore the multifaceted interactions between the microbiome, immune system, and cancer treatments, leading to richer insights and novel therapeutic strategies.

Public-Private Partnerships: Collaboration between academic institutions, biotechnology companies, and healthcare organizations can accelerate the translation of microbiome research into clinical practice. Public-private partnerships can facilitate funding, technology sharing, and the development of probiotic products tailored to oncological applications.

Global Microbiome Initiatives: Large-scale global initiatives to characterize the microbiome across diverse populations can enhance our understanding of how geographical and ethnic differences influence treatment responses. Collecting and analyzing data from various patient demographics will inform the development of universally applicable as well as region-specific probiotic interventions.

Regulatory Frameworks: Establishing clear regulatory pathways for the approval of probiotic therapies in oncology is vital. Regulatory agencies should work closely with researchers and clinicians to develop guidelines that ensure safety while promoting innovation in microbiome-based therapies.

Patient-Centric Research: Engaging patients in the research process can provide valuable insights into their experiences and needs. Patient-reported outcomes should be integral to clinical studies evaluating probiotics, ensuring that research addresses real-world concerns and enhances the quality of life for cancer patients.

Artificial Intelligence and Machine Learning Integration: Integrating artificial intelligence (AI) and machine learning (ML) in microbiome research presents great potential for improving cancer treatment. AI algorithms can analyze complex datasets including metagenomics, transcriptomics, and metabolomics to identify microbial patterns associated with response or resistance to treatment. Machine learning models can predict which probiotic strains would be beneficial for each patient based on their genetic, microbiome, clinical profile, and molecular pathological epidemiology. In addition, AI-based tools can help design personalized probiotic formulations and optimize dosing schedules by simulating host-microbiome-drug interactions. Over time, these technologies can improve the outcomes of treatment by supporting clinical decision-making and adjustments in therapy. Ultimately, combining AI and machine learning in microbiome-oncology research could accelerate discovery, leading to precise medical approaches.

The future of cancer therapy lies in a multidisciplinary approach that takes advantage of microbial complexities. Integrating tailored probiotic treatments into conventional cancer therapies can unlock new possibilities for enhancing treatment efficacy and improving patient outcomes.

In summary, the integration of probiotics into cancer immunotherapy presents a promising avenue for enhancing treatment efficacy. However, significant challenges and limitations must be addressed. Further studies are essential to fully understand the underlying mechanisms and to tailor approaches based on individual variabilities in gut microbiome. The therapeutic potential of probiotics can be maximized by prioritizing patient-specific approaches as in individualized medicine to improve the outcomes of cancer treatment. Collaboration among researchers, clinicians, and industry partners will be crucial to advancing these findings and unlocking the full potential of microbiome-based therapies in oncology.

Footnotes

Abbreviations

ORCID iDs

Amir Dayhimi

Kimia Jazi

Asiye Bigdeli

Mina Esmaeili

Marjan Ajami

Hamidreza Pazoki-Toroudi

Author’s Note

Kimia Jazi is also affiliated with School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Ethical Approval

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

All data are derived from publicly available sources cited in the manuscript.

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Harnessing the Gut Microbiome in Cancer Immunotherapy: Mechanisms,Challenges,and Routes to Personalized Medicine—A Systematic Review

Abstract

Introduction

Methods

Results

Conclusion

Keywords

Introduction

Methods and Materials

Literature Search Strategy

Inclusion and Exclusion Criteria

Data Extraction and Analysis

Ethical Considerations

Environment and Lifestyle Role in Cancer Pathophysiology

Molecular Pathological Epidemiology

Probiotics and Microbiome in Immunotherapy

Clinical Evidence: Microbiome in Cancer Immunotherapy

Challenges and Limitations

Challenges

Resistance and Treatment-Related Toxicities

Impaired Mucosal Barriers

Real-Time Monitoring

Delivery Mechanisms

Optimal Dosage and Timing

Limitations

Variability in Microbial Responses

Lack of Comprehensive Understanding

Limited Human Studies

Future Directions and Conclusion

Addressing Resistance and Toxicity and Delivery in Probiotic use

Tailoring Probiotic Treatment for Different Patients

Integrating Probiotics into Cancer Therapy: A Future Roadmap

Footnotes

Abbreviations

ORCID iDs

Author’s Note

Ethical Approval

Funding

Declaration of Conflicting Interests

Data Availability Statement

References