Microbiota and cancer: Elucidating the role of Candida albicans in cancer progression

Abstract

Candida albicans (C. albicans) represents one of the most prevalent opportunistic fungal pathogens in cancer patients. Although the association between C. albicans and cancer has been recognized for decades, the causal relationship, whether C. albicans infection is a consequence of cancer or a direct contributor to cancer development-remains a subject of intensive investigation. Recently, the complex interplay between microbes and cancer has garnered significant attention within the scientific community, with growing interest in elucidating the underlying molecular mechanisms. This review systematically examines the biological characteristics of C. albicans, its multifaceted interactions with the host, and its relationship with the intestinal microbiota. Additionally, it provides a comprehensive analysis of the association between C. albicans and the development of various malignancies, with particular emphasis on digestive tract cancers. The review also identifies critical knowledge gaps and apparent contradictions in existing research, highlighting potential avenues for breakthroughs that will advance the efficient and accurate screening, diagnosis, and treatment of cancer.

Key Words: Candida albicans; Cancer progression; Immune evasion; Inflammatory response; Tumor microenvironment

Core Tip: This review explores the role of Candida albicans (C. albicans), an opportunistic fungus, in cancer progression, particularly in digestive tract malignancies. It examines the interactions between C. albicans and the host, highlighting its relationship with the intestinal microbiota. The study also addresses the ongoing debate about whether C. albicans contributes to cancer development or is merely a complication of cancer. By identifying gaps in current research, this review seeks to open new directions for cancer screening, diagnosis, and treatment.

INTRODUCTION

The human gut microbiome comprises 10 distinct populations encompassing 14 microbial species and is frequently characterized as a “hidden organ” due to its essential functions in digestion, metabolism, and immune regulation. The dynamic interplay between the gut microbiota and its host maintains a state of homeostasis, establishing mutual dependence and sophisticated regulatory mechanisms. However, disruption of this delicate balance can adversely affect various physiological functions, including nutrient absorption, immune responses, and metabolic regulation, thereby significantly contributing to tumorigenesis[1]. In 2020, the global incidence of cancer increased substantially, imposing significant disease burden and economic costs worldwide. Studies conducted on healthy individuals do not support the existence of a core microbiome in the bloodstream, but rather suggest that symbiotic microbiota may translocate from other body regions into the circulatory system. While the precise origin of the blood microbiome remains largely undefined, current research suggests that it may primarily originate from the gut. Despite well-established associations between gut microbiota and cancer, the functional contributions of gut microbiota to oncogenesis remain incompletely characterized. As biochemical mediators, microbial metabolites function as critical intermediaries connecting the gut microbiota to cancer development[2]. Over recent decades, extensive research has elucidated the microbiome’s role in various stages of carcinogenesis, including diagnosis, progression, metastasis, and therapeutic response, with particular emphasis on bacterial and viral contributions. In contrast, the role of fungi in cancer development has received comparatively limited investigation.

Endophytic fungi constitute a significant source of specialized metabolites, characterized by diverse biological activities and complex structural properties. Notably, the investigation of cytotoxic metabolites derived from endophytic fungi has attracted substantial interest among organic chemists and pharmacologists. The crude extract of fungus F4a has demonstrated potent cytotoxic activity against KRAS mutant cells. Specifically, its primary cytotoxic component, brefeldin A, exhibited inhibitory activity in the micromolar to nanomolar range[3]. Currently, numerous research teams worldwide continue to investigate the mechanisms by which fungi contribute to cancer development, with the objective of developing effective prevention strategies and therapeutic interventions[4]. However, the complex relationship between Candida albicans (C. albicans) and various cancer types remains incompletely understood, highlighting an area of significant interest for future research.

The increasing prevalence of drug-resistant candidiasis and the emergence of multidrug-resistant Candida species presents a significant challenge to patient prognosis, particularly in immunocompromised individuals. Consequently, the treatment of biliary candidiasis has become increasingly difficult, with complete eradication often unattainable in many patients. C. albicans is the most frequently isolated species in cases of biliary candidiasis, followed by Candida glabrata[5]. Candida species can promote cancer progression through multiple mechanisms, including: (1) The production of carcinogens such as acetaldehyde, which facilitates disease development; (2) The induction of inflammatory processes that may enhance metastasis; (3) Molecular remodeling of the host environment; and (4) Modulation of the T helper cell 17 (Th17) immune response. At least 15 distinct Candida genera are known to cause disease in humans; however, the majority of invasive infections, as well as those associated with cancer, are attributed to five primary pathogens: C. albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei. Among all Candida species, C. albicans remains the most prevalent and clinically significant cause of infection, constituting part of the symbiotic microbiome in more than half of healthy individuals. The detection rate of C. albicans in candidiasis cases ranges from 70% to 90%. Due to candidemia, the mortality rate associated with C. albicans infection is significantly high, reaching 43.6%[6]. Furthermore, C. albicans exhibits greater prevalence in cancer patients compared to Candida tropicalis and Candida glabrata, primarily due to its enhanced virulence and superior biofilm-forming capacity.

Given the established association between C. albicans and cancer, coupled with the unresolved role of C. albicans in oncogenesis, this article aims to investigate whether C. albicans functions as a contributing factor in the development of various cancer types. This comprehensive review will systematically evaluate the current literature on the involvement of C. albicans in cancer and elucidate its specific molecular mechanisms in cancer progression.

INTERPLAYS BETWEEN C. ALBICANS AND HOST

Characteristics of C. albicans

A comprehensive understanding of the multifaceted characteristics of C. albicans is essential for investigating its interaction with the host. C. albicans predominantly exists in a diploid form, distinguishing it from most fungi that typically exist in a haploid state. However, recent studies have demonstrated that C. albicans can also form haploid or tetraploid states under specific environmental conditions[7]. The diploid genome of C. albicans spans approximately 29 Mb in length[8]. An intriguing and distinctive feature of C. albicans is that the amino acid encoded by the CUG codon is serine, unlike most organisms where it encodes leucine. This genetic peculiarity contributes to a prolonged heat shock response, thereby enhancing its tolerance to adverse environmental conditions[9].

C. albicans exhibits remarkable morphological plasticity, a characteristic intrinsically linked to its pathogenic potential. During infection, C. albicans undergoes significant morphological transitions, alternating between yeast, pseudohyphal, and filamentous forms. As a dimorphic fungus, it switches between yeast and mycelial states in response to environmental cues. Additionally, a phenomenon termed “high-frequency switching” has been observed, where certain strains frequently alternate between white and opaque morphologies. These morphological transitions typically occur rapidly and synchronously, but high-frequency switching occurs only in a subset of cells. These transformed cells retain the capacity for further morphological changes, rendering the process highly adaptable. The reversibility of these transformations is substantially influenced by environmental factors including carbon dioxide levels, oxygen concentration, medium composition, and temperature[10]. Traditionally, C. albicans was considered to reproduce asexually via mitosis, with no known sexual reproductive pathway. However, recent investigations have revealed compelling evidence suggesting that C. albicans can also engage in parasexual reproduction, adding complexity to our understanding of its reproductive strategies and potential for genetic diversity.

Relationship between C. albicans and epithelial barrier

C. albicans typically colonizes the skin and mucous membranes of the human body, including the oral cavity, gastrointestinal tract, anus, groin, and in healthy women, the vagina and vulva. Under normal immune conditions, it remains commensal and does not cause disease. However, multiple risk factors, such as trauma, surgery, the presence of indwelling medical devices like catheters or prostheses, reduced bacterial competition in the host niche due to antibiotic treatment, and immunocompromised states can facilitate infection through the skin and mucous membranes. The severity of infections caused by C. albicans ranges from localized mucosal infections (e.g., thrush in acquired immune deficiency syndrome patients) to life-threatening systemic infections (e.g., invasive infections in organ transplant recipients)[11]. As an opportunistic pathogen, C. albicans possesses diverse virulence factors that enable colonization, invasion, and evasion of immune surveillance, subsequently leading to infection. Major virulence factors include morphological transformation, adhesion molecules, biofilm formation, hydrolase production, and phenotypic switching[12].

Morphological transformation refers to the transition from the yeast form to the mycelial form, a critical step in C. albicans pathogenicity. In the mycelial form, C. albicans invades host tissues through active osmosis and induced endocytosis, processes regulated by several signaling pathways, with the cyclic adenosine monophosphate-dependent protein kinase A pathway being particularly crucial. Adhesion factors, a group of biomolecules expressed on the fungal surface, facilitate the attachment of C. albicans to host cells, substantially contributing to its pathogenicity. The hydrolases secreted by C. albicans, including proteases, phospholipases, and lipases, play pivotal roles in its virulence by degrading host proteins and lipids, promoting cell attachment and tissue invasion, and disrupting host immune responses.

Biofilms, which are structured communities of microorganisms encased in a protective extracellular matrix, are particularly concerning as they can lead to fatal bloodstream infections in hospitalized patients. These complex structures allow C. albicans to colonize host surfaces that individual yeast or filamentous cells alone cannot effectively inhabit. Moreover, C. albicans cells within biofilms exhibit significantly increased resistance to antifungal treatments compared to planktonic cells in culture. Biofilm formation is largely dependent on morphological transformation, as mutations that inhibit morphological switching also substantially impair biofilm formation.

Phenotypic transition refers to the switch between white and opaque cells, a process that contributes to the organism’s remarkable adaptability. This phenotypic diversity enables a rapid response to environmental changes and is vital for the survival of many microbial species. In C. albicans, switching between white and opaque forms influences filamentous growth and interaction with immune cells in vitro. These morphological and phenotypic transitions are transcriptionally stable and can persist across multiple generations, enhancing C. albicans’ ability to adapt and persist in diverse host environments[13].

Interaction between C. albicans and immune cells

C. albicans invades the human body through the action of various virulence factors. In response, innate immune cells play a crucial role in eliminating these fungal pathogens, with C. albicans being the most common cause of fungal bloodstream infections. However, the precise mechanisms by which innate immune cells recognize and clear these fungi remain incompletely characterized. The immune response to C. albicans involves pattern recognition receptors on the surface of multiple immune cells recognizing pathogen-associated molecular patterns (PAMPs) of the fungus[14]. This recognition triggers a complex and coordinated network of spatio-temporal regulation to control the infection process.

In immunocompetent individuals, epithelial barriers and innate immune responses are generally sufficient to prevent tissue invasion and infection. However, individuals with compromised immune systems are significantly more susceptible to fungal infections, with the severity depending on the extent of their immune deficiency. Candida-mediated diseases range from mild superficial infections (such as thrush in newborns) to widespread and/or recurrent infections of the esophagus or vagina. Additionally, C. albicans is associated with various inflammatory conditions, such as inflammatory bowel disease.

Innate and adaptive immune responses function synergistically against epithelial infiltration and disseminated/invasive candida infection. The initial defense mechanism is triggered by an inflammatory response mediated by the innate immune system, which subsequently induces and regulates the adaptive immune response. Adaptive immune responses play a critical role in establishing enduring defense, controlling fungal growth, restricting virulence acquisition, and preventing invasion of normally sterile tissues. The accumulation of Candida-specific Th17 cells in T-cell-mediated responses depends on homologous antigen presentation and CARD9-dependent signaling, though the complete mechanism remains to be fully elucidated. Among the various lymphocyte populations, long-lived Th17 cells residing in colonized tissues are particularly prominent, and their detailed characteristics and regulation warrant further investigation.

A recognized beneficial aspect of C. albicans colonization is the regulation of systemic Th17 immune responses, which protects immunocompetent individuals from infection. Studies have demonstrated that oscillating UME6 expression in C. albicans is essential for triggering systemic Th17 immunity during intestinal colonization. C. albicans colonization provides multiple advantages to the host, enhancing immune activation through sustained granulocyte production, amplification of circulating granulocytes and neutrophils, thereby providing cross-protection against gram-positive bacterial infections[15,16]. Furthermore, mucosal-associated fungi enhance intestinal epithelial function by inducing Th17 cells to produce interleukin (IL)-22, protecting the host from intestinal damage[9].

Homeostatic T cells play a crucial role in maintaining symbiotic immune surveillance; however, the relationship between these cells and memory T cells, which confer protection against recurrent infections, remains an area requiring further investigation. Mucosal-associated fungi, including C. albicans, mediate neuroregulation through IL-17-dependent mechanisms, with IL-17 playing non-inflammatory roles in homeostasis through processes beyond enhancing epithelial antibacterial barrier function. Antibodies are essential for maintaining homeostasis and providing protective immunity at mucosal sites as well as during systemic infections. These antibodies can be classified into five distinct isotypes, each functioning at specific sites and performing specialized effector functions. In both humans and mice, systemic antifungal antibodies, particularly the IgG isotypes, recognize a diverse array of C. albicans strains, with IgG3 demonstrating the strongest binding to intestinal fungi. IgA represents the predominant antibody isotype at mucosal barriers, primarily induced during colonization by symbiotic organisms to help maintain immune homeostasis.

The colonization of mucosal sites by C. albicans triggers multiple antibody responses that not only limit fungal overgrowth but also mitigate its virulence at both local and systemic levels. Given that C. albicans actively masks PAMPs to evade immune detection, the specific colonization patterns and corresponding exposure to PAMPs may influence immune activation, thereby facilitating the establishment of symbiotic relationships. Adaptive immunity plays a pivotal role in modulating the pathogenicity of C. albicans, and significant diversity in C. albicans hosts has been observed in humans. This diversity is particularly evident in symbiotic contexts, where genomic and epigenetic variations in C. albicans enable adaptation to environmental shifts and enhance persistence across various host niches.

Therefore, the mutual adaptations between C. albicans and mammalian hosts contribute significantly to shaping interaction outcomes at both individual and population levels. Advances in human immunology not only enhance our ability to treat diseases but also deepen our understanding of fundamental immunological principles, illuminating the relevance and role of adaptive immunity in symbiotic immune surveillance of C. albicans and the potential pathological consequences in vulnerable individuals[17]. This opens promising new avenues for studying C. albicans colonization in immunocompetent organisms and may lead to significant discoveries in the field.

Candida-microbiota interactions in the host

The environmental adaptation of C. albicans to survive within the host and its interaction with the host microbiota are pivotal for understanding fungal infection mechanisms and developing novel antifungal therapies[18]. Environmental adaptation encompasses a spectrum of responses, including stress response and metabolic reprogramming, that enhance the physiological compatibility of the fungus with its host environment. Specific genes in C. albicans are induced in response to various stressors, such as heat, osmotic pressure, and oxidative stress. Unlike Saccharomyces cerevisiae and Candida glabrata, C. albicans appears to activate a specialized core transcriptional response to osmotic, oxidative, and heavy metal stress[19].

Transcriptomic analyses have revealed that C. albicans responds to macrophage phagocytosis by activating alternative carbon metabolic pathways, including gluconeogenesis, the tricarboxylic acid cycle, and fatty acid β-oxidation. These pathways are crucial for C. albicans survival within macrophages and play key roles in its pathogenesis[20,21]. C. albicans possesses a highly plastic genome capable of facilitating rapid adaptation to environmental stress through large-scale genomic alterations, resulting in significant phenotypic variability. This stress-induced mutagenesis, driven by host innate immune responses, leads to genomic instability closely associated with C. albicans adaptation. However, the mechanistic connections between these adaptive phenotypes, genomic alterations in C. albicans, and host immunity have yet to be fully elucidated. The large-scale genomic changes induced by host-related stress may also contribute to the emergence of antifungal tolerance in C. albicans, enhancing its adaptive capacity and increasing resilience within the host environment[22].

The human microbiome constitutes a complex microbial ecosystem comprising bacteria, fungi, viruses, protists, and archaea. Among these microorganisms, fungi, particularly in the gastrointestinal tract, establish diverse relationships with other microbiota, ranging from antagonistic to symbiotic interactions. Bacterial influences on fungi manifest through direct physical contact, production of metabolites, and modulation of host immune responses, significantly affecting fungal proliferation and virulence characteristics. The bacterial community composition and their metabolic products can substantially influence the abundance, metabolic activities, and pathogenic potential of C. albicans. Furthermore, the microbiota and their secreted compounds can activate mucosal immunity and induce antimicrobial peptide (AMP) production, while C. albicans itself can elicit host immune responses, including AMP synthesis and inflammatory cytokine production.

Therapeutic approaches such as probiotics and fecal microbiota transplantation have demonstrated efficacy against C. albicans infections, with beneficial effects observed from various strains including Bacillus, Bifidobacterium, Lactobacillus, yeasts, and Metschnikowia, which inhibit C. albicans proliferation. Investigations into the intricate interactions between bacteria, fungi, and host immunity within human and murine microbiota have elucidated how these factors profoundly influence the growth, morphogenesis, and virulence expression in C. albicans, either directly or through host immune system modulation.

The microbiota potentially plays crucial roles in inflammatory, metabolic, and cognitive disorders, with emerging evidence suggesting that gut pathophysiological alterations mediate the microbiota’s impact on host behavior and neurological conditions[16]. Recent studies indicate that a balanced intestinal fungal community may contribute significantly to maintaining host immune homeostasis and overall health[23]. Substantial progress has been made in elucidating the molecular mechanisms underlying these interactions, emphasizing the necessity for future multi-microbial investigations to better comprehend the dynamic interplay between C. albicans, bacteria, and the host immune system across various host niches[18].

Genetic factors in C. albicans that influence its adaptation and morphological transitions within the host, coupled with potential therapeutic applications of probiotics, AMPs with anti-candidal activity, microbiota-derived immunomodulatory molecules, and effective bacteriological strategies such as peptidoglycan, reveal numerous promising avenues for the development of novel antifungal therapies. These approaches may target the pathogen directly, leverage host immune responses, or modulate host microbiome composition, thus establishing a foundation for innovative antifungal strategies.

IS C. ALBICANS A CONTRIBUTOR TO CANCER DEVELOPMENT?

An expanding body of research emphasizes the critical role of the microbiome in cancer diagnosis, development, progression, and therapeutic response across various malignancies[24,25]. The polymorphic nature of the microbiome is now recognized as one of the defining characteristics of cancer[26]. Advanced next-generation sequencing technologies have facilitated the identification of numerous cancer-associated microbes, supplementing the 11 established tumor-promoting microorganisms. Beyond the extensively studied bacteria and viruses, fungi-frequently overlooked-emerge as significant components of the tumor-associated microbiome[27,28]. The abundance of fungi within tumors exhibits considerable variation depending on cancer type[28].

In experimental animal models, systemic C. albicans infection has been demonstrated to induce regulatory T cell proliferation and disrupt cytokine networks, thereby promoting tumor growth[29]. However, contradictory findings have emerged, raising the fundamental question of whether C. albicans promotes or inhibits carcinogenesis. This complex issue necessitates comprehensive investigation. The following sections systematically explore recent insights into the relationship between C. albicans and various cancer types, examining its potential role in the mechanisms underlying cancer development. Table 1 summarizes the mechanisms through which C. albicans contributes to carcinogenesis.

Table 1 summarizes the mechanisms through which Candida albicans contributes to carcinogenesis[30-63].

Fungus	Associated cancer	Main hypothetical molecular mechanisms
C. albicans	Oral cancer	The main hypothesized molecular mechanisms of OC include C. albicans promoting cancer progression by producing carcinogenic byproducts, triggering inflammatory responses, inducing T-helper 17 responses, and facilitating epithelial-mesenchymal transition. Specifically, activation of the IL-17A/IL-17 receptor A-macrophage axis attracts M2-type macrophages, inducing an immunosuppressive microenvironment and promoting tumor development. Additionally, C. albicans may reduce the effectiveness of immunotherapy and influence the tumor immune microenvironment
	Esophageal cancer	C. albicans induces chronic inflammation, disrupts the esophageal mucosal barrier, promotes dysbiosis and microbial imbalance, and directly or indirectly accelerates the progression of esophageal cancer
	Gastric cancer	C. albicans reduces fungal diversity and abundance in the stomach, leading to gastric microbiome imbalance and promoting the development of GC. Additionally, its cell-free supernatant exhibits anti-tumor activity against gastric cancer cells by inducing apoptosis, inhibiting the survivin gene, and downregulating IL-8 and nuclear factor kappa-B expression, affecting inflammation and tumor growth, with potential therapeutic value
	Colorectal cancer	C. albicans activates the epidermal growth factor receptor/toll-like receptor 2-extracellular signal-related kinase/nuclear factor kappa-B-hypoxia inducible factor-1α signaling pathway, inducing a hypoxic response and promoting CRC progression. Meanwhile, studies suggest that its metabolite mixture may have a protective effect on CRC by influencing cellular energy metabolism. Additionally, C. albicans probiotics might exhibit anti-tumor effects against CRC, though the exact mechanisms remain unclear
	Breast cancer	C. albicans may influence BC by promoting tumor progression and metastasis. However, metastatic breast cancer cells have been observed to phagocytose C. albicans
	Cervical cancer	C. albicans and other microbial infections cause DNA damage and mutations, promoting CC development and increasing drug resistance

OC: Oral cancer; C. Albicans: Candida albicans; IL: Interleukin; GC: Gastric cancer; CRC: Colorectal cancer; BC: Breast cancer; CC: Cervical cancer.

Oral cancer

Oral cancer (OC) represents a significant global health challenge. According to the 2022 Global Cancer Statistics published by the International Agency for Research on Cancer, lip and OCs rank 16^th in global incidence and 15^th in mortality[30]. Among the limited evidence linking fungi to cancer, the association between C. albicans and OC has been recognized by dental clinicians for numerous years, representing a classic example of the potential connection between fungi and carcinogenesis[31]. OC, as defined by the International Classification of Diseases-10, encompasses malignant neoplasms of the lip and oral cavity. Estimates indicate that in 2020, there were 377713 new cases and 177757 deaths from OC worldwide[32]. Established risk factors for OC include tobacco smoking, betel quid chewing, alcohol consumption, and human oncoviral infection (particularly human papillomavirus)[33]. Accumulating evidence suggests that microorganisms, including Clostridium species and C. albicans, may also function as potential carcinogenic agents in OC[34]. Several mechanisms have been proposed to explain how C. albicans promotes OC, including carcinogenic byproduct production, chronic inflammation induction, Th17 response stimulation, and molecular mimicry[35]. Among these mechanisms, the production of nitrosamines[36] and acetaldehyde[37] are particularly well-documented and supported by substantial experimental evidence.

Additionally, Vadovics et al[38] demonstrated that C. albicans could enhance OC progression by inducing inflammation and altering gene expression profiles, as well as facilitating epithelial-mesenchymal transition. Another significant aspect of this relationship concerns whether C. albicans modulates the tumor immune microenvironment to promote OC progression. A recent investigation revealed that C. albicans-infected OC cells activate IL-17A/IL-17 receptor A (IL-17RA) signaling, recruiting macrophages to the tumor microenvironment. The recruited macrophages undergo polarization into M2-like tumor-associated macrophages, which upregulate programmed cell death ligand 1 and galectin-9 expression, ultimately establishing an immunosuppressive microenvironment that facilitates OC progression. These findings indicate that C. albicans contributes to OC progression via the IL-17A/IL-17RA-macrophage axis, highlighting the potential for further exploration of fungal microbiome contributions to tumor immunology[31]. This research group has also demonstrated that C. albicans overgrowth accelerates OC progression and attenuates the efficacy of programmed cell deat-1-blocking immunotherapy. They identified a potential mechanism involving the γδ T17-CCL2/CCL20-polymorphonuclear myeloid derived suppressor cells-cluster of differentiation 8+ T cell depletion axis, which may explain how C. albicans promotes OC progression[39].

Given these findings, controlling C. albicans overgrowth during cancer treatment represents a critical therapeutic consideration. The increasing resistance of C. albicans to conventional antifungal agents has stimulated exploration of alternative therapeutic approaches, such as essential oils[40-42]. Essential oil extracts, including cinnamon, laurel, and peppermint, have demonstrated antifungal activity, albeit generally less potent than conventional antifungal drugs and mouthwashes. Nevertheless, these essential oils may offer viable therapeutic options, either as monotherapy or in combination with established antifungal agents, for the treatment and prevention of oral candidiasis, particularly in patients using orthodontic appliances[43].

Esophageal cancer

Esophageal cancer ranks among the ten most prevalent malignancies globally[44], and is classified into two principal histological subtypes: Esophageal adenocarcinoma and squamous cell carcinoma. Chronic gastroesophageal reflux disease predisposes individuals to metaplastic alterations, notably Barrett’s esophagus, which significantly increases the risk of esophageal adenocarcinoma development. Distinct from this pathogenic pathway is squamous cell carcinoma, the second major subtype of esophageal cancer. Historically, the pathophysiological mechanisms affecting the esophageal mucosa were primarily attributed to acid-induced mucosal injury (i.e., reflux disease), but contemporary studies suggest a more multifactorial etiology, with the esophageal microbiome playing a central role. Specific microbial communities have been identified that may contribute to the pathogenesis of esophageal disease, and interventions aimed at mitigating dysbiosis by directly or indirectly modulating the gram-positive to gram-negative bacterial ratio may prove therapeutically beneficial. Potential therapeutic strategies include the application of prebiotics, probiotics, targeted antibiotics, and bacteriocin-based treatments.

In a related investigation, an autosomal recessive or dominant monogenic inherited disorder prevalent in Finland, known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), has been associated with a remarkably high prevalence of oral or esophageal cancer. This condition is characterized by a classic triad of autoimmune hypoparathyroidism, autoimmune primary adrenal insufficiency, and chronic mucocutaneous candidiasis, manifestations that most patients exhibit from childhood[45]. Among APECED patients over 25 years of age, oral or esophageal cancer exhibits high prevalence, with six patients in one cohort accounting for 10 percent of the total study population of 58 individuals. Early preventive measures and interventions, including meticulous oral hygiene maintenance, are strongly recommended. Dental plaque has been identified as the primary reservoir of oral yeasts, and patients with chronic disease are advised to consider topical antifungal treatments, preferentially utilizing polyene agents while avoiding azole medications[46].

Numerous studies have highlighted the emergence of antifungal resistance to azole compounds, particularly in association with multiple disease recurrences[44]. One such investigation demonstrated that quinalizarin exhibited broad-spectrum antifungal activity against all tested strains, including those resistant to fluconazole, demonstrating efficacy and low toxicity in the treatment of C. albicans and other yeast infections[6]. Another study explored the combination of oronidin (ORI) with three azole antifungals-fluconazole, itraconazole, and voriconazole-revealing synergistic interactions that enhance the susceptibility of azole-resistant C. albicans to these agents. Moreover, ORI was found to inhibit drug efflux mechanisms and promote cellular apoptosis, suggesting novel approaches for addressing the increasing problem of azole resistance in C. albicans[47].

Gastric cancer

Gastric cancer (GC) ranks as the fourth most prevalent malignancy and represents one of the leading causes of cancer-related mortality worldwide. Over the past decade, research on the gastric microbiome has been relatively limited due to technical challenges associated with cultivating the commensal microorganisms that inhabit the stomach. Consequently, investigations of the gastric microbiome have lagged behind those of the intestinal microbiome, although scientific interest in this field has recently intensified. While Helicobacter pylori infection remains a well-established risk factor for histopathological alterations in the gastric mucosa, the incidence of GC following infection is not particularly high, suggesting that other microbial components may play critical roles in GC pathogenesis. With the advent of high-throughput sequencing technologies, comprehensive exploration of the gastric microbiome has become feasible. Recent research has elucidated the characteristics of the fungal microbiome in gastric tissue from GC patients, revealing that dysbiosis in the gastric fungal ecosystem, particularly involving C. albicans, may contribute to GC development by reducing fungal diversity and abundance in the stomach, thereby facilitating disease progression. Additionally, C. albicans has been identified as a potential non-invasive biomarker with notable diagnostic accuracy for GC detection[48]. A recent investigation demonstrated that cell-free supernatant from C. albicans cultures exhibited significant antitumor activity against both conventional and drug-resistant human GC cell lines (EPG and RDB cells, respectively). The treatment induced apoptosis via caspase activation, inhibited survivin gene expression in both cell lines, and downregulated IL-8 and nuclear factor kappa-B (NF-κB) gene expression in conventional GC cells[49].

Colorectal cancer

Colorectal cancer (CRC) ranks as the fourth most common malignancy and the second leading cause of cancer-related mortality globally. Although limited, several studies have examined the relationship between C. albicans and CRC pathogenesis. Evidence suggests that the presence of C. albicans in the intestinal microbiota may contribute to the initiation or progression of certain sporadic CRC cases[50]. A recent investigation demonstrated that C. albicans activates the epidermal growth factor receptor/toll-like receptor 2-extracellular signal-related kinase/NF-κB-hypoxia inducible factor-1α signaling pathway, triggering hypoxic responses that accelerate cancer progression[51]. However, contrasting findings have emerged from other studies. One investigation indicated that Lactobacillus plantarum and C. albicans probiotics, isolated from the gastrointestinal tract of elderly individuals, may play protective roles against CRC in animal models, although additional research is necessary to validate the antitumor effects of these probiotics in human subjects and across diverse cancer types[52]. Additionally, this research group discovered that a mixture of C. albicans metabolites exerts protective effects against CRC initiation and progression, demonstrating dynamic interactions with cellular bioenergetics[53,54].

While the association between mycobiome dysregulation and CRC is evident, the complexity of the intestinal microbiota and limited understanding of its comprehensive impact make it challenging to definitively determine whether mycobiome alterations represent causative factors or consequences of CRC pathogenesis. In future applications, identification of fungal dysbiosis patterns in CRC may offer promising opportunities for early screening and diagnosis. Furthermore, targeted modulation of the gut microbiota through dietary interventions, probiotic/prebiotic supplementation, or fecal microbiota transplantation could provide potential strategies for CRC prevention. A more comprehensive understanding of microbiota contributions to CRC may establish the foundation for innovative therapeutic approaches[55].

Recent metabolomic analyses have identified several compounds that show increased concentrations in the presence of C. albicans, including Galβ1, 3GlcNAc, 3-methoxytyramine, propacetamol hydrochloride, sphingosine 1-phosphate (S1P), genistein, propofol glucuronide, luffariellolide, carbaryl, galangin, and neopine[54]. S1P is a bioactive lipid generated through degradation of endogenous and dietary mammalian sphingolipids containing long-chain sphingosine bases. S1P activates NF-κB and signal transducer and activator of transcription 3, two transcriptional regulators that function as master switches in inflammatory processes and carcinogenesis[56]. Genistein has been shown to inhibit human CRC growth and suppress miR-95, protein kinase B, and SGK1 signaling[57]. The metabolite mixture produced by C. albicans may further inhibit CRC development through the secretion of bioactive compounds.

Breast cancer

Breast cancer represents the most prevalent malignancy among women globally, with its incidence notably increasing among women under 40 years of age, particularly in the United States and Asia[58]. In 2022, there were approximately 2.3 million new cases of breast cancer and 670000 associated deaths among women worldwide[59]. This cancer type demonstrates high susceptibility to Candida infection, and emerging evidence suggests that candidiasis may exacerbate tumor progression and metastatic dissemination[60,61]. In vitro studies have demonstrated that metastatic breast cancer cells exhibit phagocytic activity against C. albicans[62]. The concurrent presence of breast cancer and candidiasis presents a significant clinical challenge. Recent investigations into novel small molecule inhibitors targeting both bromodomain and extraterminal domain proteins and histone deacetylases have explored their potential for combination therapy addressing both breast cancer and drug-resistant C. albicans infections. These dual-targeting inhibitors have demonstrated superior antitumor efficacy in vivo compared to monotherapeutic approaches, offering promising therapeutic prospects[60].

Cervical cancer

Cervical cancer remains a leading cause of mortality and morbidity among women globally, claiming millions of lives annually. Despite substantial progress in diagnosis, prevention, and treatment modalities, mortality rates remain alarmingly high, particularly in low-income countries. Various risk factors contribute to the incidence of both colorectal and gynecological cancers, including persistent infection with high-risk human papillomavirus, excess adiposity, unhealthy lifestyle behaviors, and socioeconomic disadvantage. Additionally, certain bacterial, fungal, and viral infections have been demonstrated to induce DNA damage and mutational events, thereby increasing cancer susceptibility. Epidemiological data indicate that approximately 700000 individuals worldwide succumb annually to infections caused by multidrug-resistant microorganisms. Recent investigations have identified that the principal active constituents of cumin oil-cumin alcohol and cuminal-possess potent anticancer properties. Moreover, the antibacterial efficacy of cumin against various human bacterial pathogens, including Candida species and multidrug-resistant bacteria, has been demonstrated through advanced computational molecular docking approaches, suggesting promising therapeutic applications for future clinical implementation[63].

Lung cancer

Lung cancer represents a leading cause of cancer-related mortality among women in numerous countries, including the United States. It is estimated that 1.8 million individuals die from lung cancer annually worldwide, accounting for 18% of all cancer-related deaths, establishing it as the predominant cause of cancer mortality[64]. Clinical studies have reported that 13.9%-42.9% of lung cancer patients exhibit colonization with C. albicans in their bronchial tree[65]. Bronchial colonization is frequently documented in lung cancer patients and may have important implications for treatment strategies and prognostic outcomes. A prospective investigation involving 210 consecutive lung cancer patients undergoing diagnostic flexible bronchoscopy revealed C. albicans colonization in 42.9% of cases[66]. In vitro studies suggest that β-glucan extracted from C. albicans may exhibit anticancer effects by enhancing apoptotic mechanisms in lung cancer cells and suppressing the expression of metastasis-associated genes in the Lewis lung carcinoma (LL/2) cell line[67,68]. C. albicans-derived β-glucan functions as a novel regulatory factor in the tumor microenvironment, targeting macrophage polarization and inducing ferroptosis in lung cancer[69].

CONCLUSION

The human body harbors a diverse ecological community of microorganisms across cutaneous and mucosal surfaces, with bacteria, viruses, and fungi all exhibiting potential associations with carcinogenesis. A delicate homeostasis is maintained between the microbiota and the immunocompetent host. C. albicans, a ubiquitous opportunistic fungal pathogen, can transition from a commensal organism to a virulent pathogen when host immune surveillance is compromised or under specific predisposing conditions. The impact of C. albicans on human physiology is particularly evident within the gastrointestinal tract. Research investigating the relationship between C. albicans and cancer has predominantly focused on digestive system malignancies, including oral, esophageal, gastric, and colorectal, cancers, with these neoplasms demonstrating relatively stronger associations with C. albicans colonization and infection. In cancers associated with the female genital tract mucosa, such as cervical cancer (which is primarily attributable to human papillomavirus infection in approximately 90% of cases), investigations examining the role of C. albicans remain limited. Similarly, other prevalent malignancies, including breast, hepatocellular, and lung carcinomas, have received insufficient attention regarding potential C. albicans involvement; however, in oncology patients, particularly those with immunosuppression or multidrug-resistant disease, complications arising from invasive C. albicans infections represent significant clinical challenges. Research examining the relationship between C. albicans and cancer has generated conflicting evidence. While certain studies suggest that C. albicans may enhance cancer progression through various mechanisms, others indicate that its metabolic products or cell-free supernatants can inhibit neoplastic cell proliferation. Therefore, further comprehensive investigation into the biological characteristics of C. albicans, its infection mechanisms, host-pathogen interactions, and its interplay with other microbiome constituents is essential for developing precise diagnostic, screening, and therapeutic strategies.