Fungal influence on immune cells and inflammatory responses in the tumor microenvironment (Review)
- Authors:
- Published online on: November 11, 2024 https://doi.org/10.3892/ol.2024.14796
- Article Number: 50
Abstract
Introduction
Human microbiota
The human microbiota comprises diverse microbial communities that inhabit various regions inside and outside the human body. These communities include bacteria, fungi and viruses (1). These microbiota colonize distinct anatomical sites such as the oral cavity (2), skin (3), intestinal tract (4), reproductive tract (5) and even the brain (6). Each anatomical site provides a unique physiological environment, fostering the growth and proliferation of specific microorganisms tailored to those conditions (7,8). Consequently, every part of the body harbors its own distinct microbial community. Disruptions in the regulatory mechanisms that govern the microbiota of the host, whether caused by infections, dietary changes or lifestyle factors, can disturb the delicate balance between the microbiota and the host (9). These disturbances often result in dysbiosis, marked by an imbalance in the microbial composition within the body. Dysbiosis can manifest in various ways, including alterations in the abundance of specific microbial taxa, changes in microbial diversity or shifts in the metabolic activities of the microbiota (10). This dysbiotic state can have significant implications for human health, as it is increasingly recognized to contribute to the development or progression of various diseases, such as colorectal cancer, inflammatory bowel disease, and non-alcoholic fatty liver disease (11,12).
Tumor microenvironment (TME)
The concept of the TME was organically proposed by Stephen Paget, an assistant surgeon at the Royal London Hospital, over a century ago (13). Paget introduced the ‘seed and soil’ hypothesis of cancer, suggesting that the microenvironment surrounding tumors play a critical role in their growth and spread. TME refers to the intricate milieu in which tumor cells reside (14). It includes surrounding blood vessels, immune cells, fibroblasts, myeloid-derived inflammatory cells, various signaling molecules and extracellular matrix (ECM) (15). It serves as a dynamic ecosystem that influences the survival and progression of tumor cells. The interplay between tumor cells and immune cells, along with the complex signaling networks and molecular interactions, profoundly shape the fate of the tumor (16).
The present review focuses on the interaction between fungi and inflammatory response within the TME. Specifically, this study explores the potential role of fungi in tumor development through their interactions with immune cells. Understanding these interactions may offer novel insights into innovative therapeutic strategies that target TEM.
Relationship among human microbiota, TME and tumors
Recent advancements in molecular biology, genomics and high-throughput sequencing technology have shed light on the critical role of the microbiota in maintaining organismal homeostasis and influencing cancer development (17). The contribution of microorganisms and microbiota to carcinogenesis can be broadly categorized into altering the balance of host cell proliferation and death, modulating immune system function, and influencing host metabolism (11). Notably, certain microbial species, such as pks+ Escherichia coli and Clostridium nucleatum, have been implicated in colorectal carcinogenesis through modulating the TME and directly inducing gene mutations in epithelial cells (18).
Although bacteria and viruses have been extensively studied in relation to cancer (17), fungi have received less attention. Emerging evidence highlights the importance of fungi in cancer development by influencing the TME (19,20). A comprehensive study analyzing the mycobiomes of 17,401 tissue and blood samples across 35 cancer types has revealed a noteworthy positive correlation between fungal communities and cancer incidence (21). This finding emphasizes the potential role of fungi in tumorigenesis across diverse cancer types. Fungi exhibit heterogeneous distributions within different cancers, suggesting a nuanced relationship with the progression of specific tumor types. This variability in fungal presence and abundance highlights the complexity of their interactions within the TME and their potential impact on tumor behavior (22).
While the precise mechanisms by which fungi contribute to cancer development are still being elucidated, several fungi have been implicated in this process. Candida albicans, Malassezia spp., and Aspergillus spp. have garnered attention for their potential roles in oral squamous cell carcinoma, pancreatic ductal adenocarcinoma and lung adenocarcinoma. These fungi, along with others that yet to be fully characterized, represent intriguing targets for further investigation into their mechanisms of action and their implications for cancer development.
Candida albicans and cancer
The association between Candida spp. and gastrointestinal cancers, particularly gastric (23) and colon cancer (24), have been documented. Candida albicans, a common fungus in the human body, is typically found as a commensal organism, mainly in the colon and vagina. However, when the disturbance in the host-fungus balance can lead to excessive growth of C. albicans, leading to various health issues such as serious candidiasis (25) and current vulvovaginal candidiasis. The potential link between C. albicans and oral tumors was first observed in the 1960s (26). Subsequent reports have strengthened the evidence, suggesting a correlation between the presence of C. albicans in the oral mucosa and the development of oral squamous cell carcinoma (OSCC) (27–29). The association between C. albicans and OSCC is an example of explored fungus-cancer connections, the evidence for such associations (30–32). Abnormal colonization of the intestine by C. albicans and Malassezia furfur promotes the development and progression of HCC. In the integrated experiment, compared with the control group, the weight and volume of HCC tumors in the Candida albicans and Malassezia furfur groups significantly increased (33).
Malassezia and cancer
The connection between Malassezia and cancer, particularly pancreatic ductal adenocarcinoma (PDA), has been highlighted in a case report from 2022 (34) The report observed a significant increase of ~3,000-fold in the number of fungi in PDA compared with normal pancreatic tissue in both humans and mice subjects (34). To further investigate this relationship, researchers established models of slowly progressive and invasive PDA. The authors revealed that removing the mycobiome (the fungal community) protects against tumor growth, whereas re-introducing Malassezia accelerates oncogenesis, potentially through the glycans of the fungal wall binding to mannose-binding lectin, activating the complement cascade (34) and accelerating pancreatic cancer progression (35). Other experiments also confirmed that fungal pancreatic carcinogenesis occurred due to the activation of the complement cascade and the secretion of IL-33 and IL-6 (36,37).
In addition to PDA, elevated levels of Malassezia are also found in intestinal mucosa samples from patients with Crohn's disease compared with healthy individuals. Crohn's disease is closely associated with the development of colorectal cancer (CRC). This finding suggests the potential for early CRC diagnosis by assessing the presence of Malassezia in intestinal mucosa samples (38).
Aspergillus and cancer
The aflatoxin produced by Aspergillus flavus has confirmed to be one of the most potent natural carcinogens, known to cause liver cancer. Since its association with live cancer was first reported in 1990, researchers have extensively explored the potential mechanisms by which this fungus acts as a carcinogen (39). Through the use of Multicohort Fecal Metagenomic Analytics, scientists have also identified an association between Aspergillus lambellii and CRC (40).
However, current research primarily focuses on investigating the differences in Aspergillus abundance in the feces of patients with CRC compared with healthy individuals. While it has been established that fungi, including Aspergillus lambellii, can serve as biomarkers for CRC diagnosis, the specific mechanisms underlying this relationship are not yet fully understood (40). In the exploration of the correlation between Aspergillus and lung adenocarcinoma (LUAD), researchers have observed an enrichment of tumor resident Aspergillus not only in patients with LUAD, but also in three distinct homologous lung cancer mouse models. Through these models, it has been found that Aspergillus promotes lung tumor progression by mediating the expansion and activation of myeloid-derived suppressor cells via IL-1β signaling (41). How does this fungus activate the signaling pathway, as shown in Fig. 1. This process inhibits cytotoxic T lymphocytes activity and impedes the accumulation of PD-1+CD8+T cells (41), thereby facilitating tumor growth.
Other fungi and cancer
In addition to well-known fungi such as Malassezia, C. albicans and Aspergillus, other less common fungi species have also been contributed to tumor occurrence and development through dysbiosis of the microbial community. Advanced sequencing technologies such as whole-genome shotgun sequencing and high-throughput sequencing have been used by research to identify changes in these fungi in tumor patients compared with healthy individuals. For instance, there is an observed increase in the abundance of Trichophoron and Malassezia in the intestinal mucosa of patients with CRC (42), as well as Nakaseomyces and Skeletocutis in patients with pancreatic ductal adenocarcinoma (43). Aspergillus lambellii is closely related to the CRC-enriched bacterium Fusobacterium nucleatum, and this type of fungi can promote CRC cell proliferation and tumor growth in xenograft mice (40). Through pan-pathogen array (PathoChip), the 18S ribosomal RNA signal of dendritic spores has been detected in almost all ovarian cancer samples, in addition to the distinctive features of Pneumocystis, Acremonium, Cladophialophora, Malassezia and Pleistophora microsporidia (44). It has been revealed that >95% of ovarian cancer samples correlate with the features of Rhizomucor, Rhodotorula, Alternaria and Geotrichum, but the features of Geotrichum are also detected in all control samples (44). Thus, all the aforementioned mentioned fungi except Geotrichum deserve to be noticed in ovarian cancer.
Although these findings warrant further investigation, they underscore the importance of analyzing fungal dysbiosis in comprehending the mechanisms underlying cancer occurrence. Recent studies have also suggested an association between certain fungal species and tumor transcriptional profiles (21,22) or CRC stage (22,45), but a specific causal relationship is unknown.
While the link between these less common fungal species, as shown in Table I, and carcinogenesis may require further confirmation through additional clinical studies, it is evident that the relationship between tumors and fungi is intricate. Dysbiosis of fungi can significantly impact the immune response within the tumor microenvironment, thereby influencing tumor occurrence and progression.
Effect of immune cells induced by fungi in the TME
Fungi can elicit various immune responses within the TME through interactions with immune cells. The presence of fungi in the TME can activate immune cells, leading to both pro-inflammatory and anti-inflammatory responses.
Mast cells (MCs)
MCs are important resident sentinel in TEM, recognizing fungal cells and playing a crucial role in the immune response. The response of MCs to fungal cells depends on their morphology and MC subtype (46). Connective tissue mast cells predominantly respond to the mycelial state of C. albicans by promoting the production of anti-inflammatory cytokines (47). By contrast, mucosal mast cells (MMC) tend to react differently, promoting death and damage in response to yeast state of C. albicans (48).
During C. albicans infection in vivo, mast cells exhibit a dual role. They contribute to the initial inflammatory pathology (48,49) while also playing a crucial role in controlling fungal growth and spreading, as well as activating the Th1 immune response for memory protection during reinfection (49). In leaky gut models, Candida-driven IL-9 and MMC contribute to the loss of barrier function, dissemination of the fungus (50) and inflammation (51,52). This highlights the ability of C. albicans to exploit the versatility of the IL-9/MC axis for both symbiosis and pathogenesis. The IL-9/MC axis, by integrating signals from disturbed host/microbiota homeostasis, may serve as a marker for distinguishing between pathogenic and protective roles of fungi in the gut (49).
Candida-infected MCs have been shown to enhance the crawling ability of macrophages and to promote their chemotaxis towards the site of infection, suggesting an important role in modulating macrophage responses during C. albicans infections (53). As MCs maintain equilibrium between the host and commensal fungi such as C. albicans, their modulation of macrophage activity would likely helps limit fungal growth during infections (54). However, quiescent MCs can notably inhibit phagocytosis of C. albicans by macrophages in a contact-dependent manner (47). This property may indeed be implicated in suppressing macrophage activity, potentially aiding in immune evasion within the tumors.
Neutrophils
Neutrophils are an essential component of the innate immune system, equipped with both neutrophilic and specialized granules that aid in the digestion of bacteria and foreign bodies. They possess strong chemotaxis and phagocytosis capabilities, making them quick response at fungal infection sites (55). Studies have also found that neutrophils have a close association with tumor development in the TME (56–58). Depleting neutrophils leads to increased tumor growth, proliferation and invasiveness in mouse model of inflammation-induced and sporadic colon tumors (59).
Candidalysin, a peptide toxin secreted by C. albicans, play a crucial role in the interaction between the fungus and host cells. Candidalysin activates the EGFR-ERK pathway in a ligand-dependent manner (60), leading to the release of transcription factor c-Fos, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. These factors are essential for recruiting neutrophils to clear infections and can also promote cancer development.
While neutrophils are generally associated with anti-tumor activity due to their ability to eliminate pathogens and produce cytotoxic molecules, the potential influence of C. albicans on the TEM through its interaction with neutrophils via candidalysin secretion raises intriguing questions (61). It is plausible that C. albicans could modulate the TME to promote tumor progression by exploiting its interaction with neutrophils.
Macrophages
Macrophages are known as the first line of defense against pathogens. They are responsible for recognizing, phagocytosing and degrading cellular debris and pathogens. Additionally, they play a crucial role in presenting antigens to T cells and inducing the expression of co-stimulatory molecules by other antigen-presenting cells (62). Recent research has revealed a dichotomy in macrophage polarization, identified as two distinct forms: M1 and M2. M1 macrophages produce type I pro-inflammatory cytokines, participate in antigen presentation and exert an antitumor role (63). Conversely, M2 macrophages produce type II cytokines that promote anti-inflammatory responses and possess pro-tumor functions (64). In fact, macrophages play a pivotal role in supporting various aspects of tumor progression and tumor cell invasion (65).
Mechanistically, it has been discovered that phenylpyruvic acid derived from C. albicans directly binds to sirtuin 2, leading to an increase in reactive oxygen species (ROS) production (66). ROS, in turn, modulate various cellular signaling pathways primarily involving transcription factors NF-κB and STAT3 (67), hypoxia-inducible factor-1α (68), kinases, growth factors, cytokines and other proteins and enzymes. These pathways have been implicated in various aspects of cancer biology, including cellular transformation, inflammation, tumor survival, proliferation, invasion, angiogenesis and metastasis (69,70). In a mouse model lacking the c-type lectin Dectin-3 (Dectin-3-/-), increased C. albicans load triggers glycolysis in macrophages and secretion of IL-7, which induces IL-22 production in type 3 innate lymphoid cells (ILC3) via the aryl hydrocarbon receptor and STAT3 signaling pathway (71). Notably, IL-22 has been shown to promote tumor growth in several models (72,73). This aligns with the fact that IL-22 is a potent activator of STAT3 in epithelial cells (74), which is required for the development of colitis-associated cancer (75). Based on these findings, it is reasonable to speculate that C. albicans promotes macrophages activation via the IL-22/STAT3 axis, contributing to the complex interplay between fungal infection and cancer development.
Similar effects on macrophages have been reported in another yeast species, including Malassezia. The enrichment of Malassezia in fungal communities found in mouse and human pancreatic tumors suggests a potential carcinogenic role for this organism (31), possibly through its influence on the immune system of the host, such as suppressing immunity via the inhibition of M1 macrophage differentiation. Therefore, targeting fungal populations such as Malassezia or modulating inflammatory responses associated with these fungi may hold significant promise in reshaping the TEM and enhancing cancer immunotherapy. By disrupting the immunosuppressive effects of these fungi, it may be possible to enhance the antitumor immune response and improve the effectiveness of immunotherapy for cancer treatment.
Dendritic cells (DCs)
DCs play a crucial role in both initiating the primary host immune response and enhancing the secondary host immune response. As the most potent antigen presenting cell, DCs excel at stimulating the activation and proliferation of naive T cells, making them primary initiators of specific immunity.
Recent findings have revealed that the yeast form of C. albicans induces Th17 cell responses through a mechanism that requires Dectin-1-mediated expression of IL-6 by DCs (76). This underscores the potential of DCs to not only mediate immune responses to fungal infections but also to exert influences on the TEM. However, despite the critical role of DCs in promoting T cell responses (77), the interaction between fungi and DCs within the TME remains relatively unstudied. Understanding the dynamics of this interaction, along with the broader interplay between tumors, immune cells and fungi in the TME, will continue to be a prominent focus in future studies.
Natural Killer (NK) cells
In recent years, the importance of NK cells in antifungal immunity (43,78) has been recognized, in addition to their well-known role in combating viruses and tumors. While NK cells are capable of recognizing and eliminating C. albicans, fungal cells can also inhibit NK cells by manipulating the immune checkpoint receptor T cell immunoreceptor with Ig and ITIM domains in both humans and mice (79). Despite this emerging understanding, there is a lack of studies investigating in the interaction between NK cells and C. albicans within TME. More in-depth research is needed to further explore this interaction.
T cells
Regulatory T cells (Treg cells)Treg cells, a subpopulation of CD4+ T cells, play a crucial role in immune homeostasis by preventing autoimmunity, controlling excessive inflammation and maintaining immune tolerance. In normal physiological conditions, Treg cells regulate the proliferation and activation of T and B cells, as well as the homeostasis of innate cytotoxic lymphocytes (80). However, the immunosuppressive effect of Treg cells can lead to immune escape of tumor cells, indirectly promoting tumor cell proliferation and enhancing tumor cells infiltration capacity (81).
In a study by Ahmadi et al (82), mice were divided into four groups: Normal, tumor, Candida infected and tumor/Candida groups. The results demonstrated that Candida infection led to an increase in the Treg population in the TME in the experimental group compared with the uninfected control group. Similarly, in a mouse model of lung cancer constructed by Liu et al, a higher proportion of Tregs was observed in the TME of mice exposed to Aspergillus sydowii (41). These experiments collectively suggest that fungi may contribute to the occurrence and development of tumors by inhibiting antitumor immune responses through mechanisms involving Treg cells. However, the specific signaling pathways and mechanisms underlying this response remain unclear and warrant further investigation. Understanding these mechanisms could provide insights into potential therapeutic strategies for targeting fungal-induced immunosuppression in cancer.
T helper (Th)2 cells
Th2 cells and ILC2 have been shown to stimulate tumor growth by secreting pro-tumorigenic cytokines such as IL-4, IL-5 and IL-13 (83). Notably, the cancer-cell-specific deletion of IL-33 has been found to reduce the recruitment Th2 and ILC2, thereby promoting tumor regression (84,85). Notably, the secretion of IL-33 has been found to be dependent on the intra-tumoral fungal mycobiome (86). Specifically, Malassezia in the pancreas has been implicated in promoting the occurrence of pancreatic tumors by promoting the secretion of IL-33. Genetic deletion of IL-33 or anti-fungal treatment can decrease TH2 and ILC2 infiltration and increases survival (84).
According to a 2016 report, all cases of atrophying pityriasis versicolor had Malassezia infiltration within the stratum corneum and were surrounded by focal interfacial dermatitis mediated by Th2 cell (87). These findings may reveal the generation of Malassezia-primed Th2 cells.
Th17 cells
C. albicans regulates Th17 cells proliferation, leading to increased secretion of IL-17A, IL-17F, and IL-22. IL-17 activates NF- κB through the MAP kinase pathway, enhancing its biological activity (88). IL-17A is a pro-inflammatory cytokine that recruits neutrophils and promotes their proliferation, maturation and chemotaxis. It also synergistically activates T cells and promote cell maturation (89).
A recent study revealed that C. albicans infection induces the expression of Gasdermin E (GSDME) in a specific subset of human Th17 cells (90). GSDME is a membrane pore-forming molecule that induces rapid cell death, suggesting its potential role as a cancer checkpoint (91). Investigating GSDME expression on the surface of Th17 cells following C. albicans infection could provide valuable novel insights for tumor diagnosis. Further research is required to explore the implications of C. albicans-mediated GSDME response on Th17 cells within TEM. Understanding the impact of ton tumor development, progression and therapy response could lead to innovative approaches to cancer diagnosis and treatment (90).
CD8+ T cells
CD8+ T cells play a key role in eliminating intracellular infections and malignant cells and provide long-term protective immunity (92). There are multiple subpopulations of CD8+ T cells, each with distinct effector functions and cytotoxic potential; for example, Tc1s has special cytotoxic activity and can effectively kill tumor cells and cells containing intracellular pathogens (93). Tc17 can produce IL17, which acts on tumor cells or other cells within the TME (94). These subpopulations have also been detected in the TME (95)
On the other hand, CD8+ T cells themselves can target the fungus to produce and secrete large amounts of IFN-γ and protease granzyme B to control the infection (96). For example, in a mouse model of lung adenocarcinoma, the proportion of CD8+ T cells in the TME increased after Aspergillus sydowii infection, revealing that CD8+ T cells and fungi reach a delicate balance in the TME to regulate tumor development (41).
Future perspectives
The presence of specific fungi within the TME holds promise as novel diagnostic or prognostic marker for specific types of cancer. Recent research by Narunsky Haziza et al in 2022 investigated the relationship between clinical data of various cancer patients and fungal species, revealing positive associations between fungi and various clinical outcomes. For instance, fungi were found to be positively associated with total survival time of patients with breast cancer, progression free survival time in patients with ovarian cancer, immunotherapeutic response in patients with melanoma and detection of early cancer (21). These findings suggest that fungi could serve as valuable biomarkers and potential therapeutic targets in cancer management. The analyses of gut microbiota as a screening, prognostic or predictive biomarkers have already begun to meet clinical applications, offering a promising avenue for preventing cancer, enhancing treatment efficacy and reducing adverse treatment effects through microbiota regulation (97).
Recent studies have also highlighted the significant role of fungi in cancer treatment and drug resistance. In addition to the direct approach of reducing Th2 and ILC2 infiltration through antifungal therapy, which can improve the survival rate of patients with cancer (86), the use of some fungal metabolites, such as polysaccharides and triterpenes, in conjunction with immune therapy, has garnered attention for their antitumor effects through various mechanisms (98). Polysaccharides can serve as key antitumor metabolites in numerous fungi infections through their impacts on host immunity. They exhibit diverse effects on host immunity by enhancing immunity, inhibiting tumor cell growth and inducing tumor cell apoptosis (99). Polysaccharides derived from Ganoderma atrum have been reported to activate macrophages, improve immunity and inhibit colorectal tumor growth through a TLR4 dependent signaling pathway (100). In addition to inhibiting tumor growth, Ganoderma polysaccharides have shown promise in antihepatocellular cancer treatment by modulating macrophage polarization (86) or increasing the ratio of the effector T cells to Tregs (101). Another example is Poria cocos polysaccharides, which have been implicated in exerting antitumor effects. According to experiments conducted by Jing et al, Poria cocos polysaccharides have the ability to induce apoptosis in ovarian cancer cells (102).
Triterpenes represent another common antitumor component found in fungi. Feng et al (103) studied the inhibitory effects of Ganoderma triterpenoids on cell proliferation and tumor growth, revealing their ability to induce cell death in lung cancer cells in vitro. Additionally, in a Lewis tumor-bearing mouse model, Ganoderma triterpenoids significantly delayed its tumor growth (104). Although research on this ingredient primarily focuses on in vitro and mouse experiments, lacking clinical trial data, its potential therapeutic effects warrant further exploration. Investigation whether Ganoderma triterpenoids has a specific effect on the treatment of patients with lung cancer is an important step for future exploration. Furthermore, assessment of their safety and toxicity are also worth further research. However, regardless, the combined use of these products in clinical settings is also essential.
Anticancer drug resistance is present in almost all types of cancers (105). Research on the relationship between the immune microenvironment and tumor resistance is advancing rapidly. T-cell depletion is a well-documented factor in promoting resistance to anticancer drugs, and strategies to enhance T-cell infiltration show promise in overcoming this anticancer drug resistance. Notably, fungi have been increasingly recognized for their influence on immune function and their potential role in cancer treatment. A study utilizing a fecal microbiota transplantation to boost the effectiveness of PD-1 therapy in drug-resistant melanoma patients marks a significant breakthrough (106). It underscores the potential for manipulating the microbiome, including fungi, to enhance responses to immunotherapy (107). As research continues to uncover fungal-bacterial communities capable of significantly improving tumor treatment outcomes, there is hope for extending these benefits beyond melanoma to other cancer types treated with antitumor therapies.
Both animal experiments and clinical studies have found the significant impact of gut microbiota (108) on enhancing the anticancer effects of checkpoint inhibitors such as CTLA-4, PD-1, and PD-L1 in treating lung cancer (109), renal cell carcinoma (110) and melanoma (106,107,111). Changes in gut microbiota appear to enhance the effectiveness of PD-1 inhibitors by possibly activating the IL-12 signaling pathway, which boosts the response of Th1 cells and activates T lymphocytes (108). Modulating the proportion of probiotics and fungi within the gut microbiota, potentially through antifungal drugs, could further optimize the efficacy of PD-1 inhibitors.
Numerous studies have demonstrated the capacity of gut microbiota to influence the body's immune function and bolster the efficacy of immunotherapy, indicating that manipulating gut microbiota could emerge as a crucial element in tumor prevention and immunotherapy (81,112,113). The highlighted therapies underscore the significant interplay between fungi and the immune system, presenting considerable promise in tumor prevention and treatment. However, it is essential to conduct additional clinical trials to confirm the efficacy and safety of these approaches.
Conclusions
In conclusion, the relationship between fungi, immunity and the TEM is intricate and significant. Fungi possess the ability to modulate immunity through diverse mechanisms, consequently influencing the TME. The cytokines produced by different immune cell phenotypes play a crucial mediator in determining tumor outcomes.
Studying the interaction between the tumor immune system and microbiota holds promise for uncovering novel therapeutic targets. It is essential to gain a deeper understanding of molecular mechanisms underlying fungal actions in tumors. This knowledge will contribute to the discovery of novel therapeutic targets and such endeavors will not only facilitate the discovery of new therapeutic targets but also aid in identifying valuable biomarkers for improved cancer treatment strategies.
Acknowledgements
Not applicable.
Funding
This work was supported by grants from the National Nature Science Foundation of China (grant no. NM 82272358), the Key Research and Development Plan of Jining (grant nos. NM 2023YXNS001 and NM 2022YXNS127) and the Medicine health science and Technology Development Plan of Shandong Province (grant no. 202202070556).
Availability of data and materials
Not applicable.
Authors' contributions
JZ wrote the original draft. YF participated in the revision of the draft manuscript. DM supervised the study, visualized the data, and reviewed and edited the manuscript. DS provided resources, visualized the data, and reviewed and edited the paper. All authors read and approved the final version of the manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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