Head and neck cancer (HNC) arises from epithelial cells and occurs in various anatomical localizations of the upper aerodigestive tract. HNC is the sixth most common cancer worldwide (Johnson et al., 2020). Although treatments have evolved considerably over the years, the quality of life and long-term survival of patients treated for HNC remain poor. Thus, it is crucial to explore the pathogenesis and the means of early diagnosis of HNC to achieve its effective prevention and control. Saliva diagnosis is a fast-evolving field, particularly in HNC. Recently, Mohamed et al. (2021) explored the potential value of the mycobiome in the saliva of patients with oral squamous cell carcinoma (OSCC). Kaplan-Meier survival analysis showed that higher Candida carriage was notably related to a shorter overall survival (OS). In contrast, higher salivary Malassezia carriage was remarkably correlated with favorable OS in patients with OSCC. The Cox proportional hazards multiple regression model (adjusted for age) revealed that Malassezia was an independent predictor of OS (Mohamed et al., 2021). Interestingly, a recent study confirmed that sublingual application of Candida or D-zymosan significantly accelerated and worsened tongue dysplasia and hyperplasia (Bhaskaran et al., 2021). Moreover, the enrichment of Candida albicans has also been correlated with an increase in the inflammatory cytokines interleukin (IL)-1β and IL-8 in the saliva of patients with head and neck squamous cell carcinoma (HNSCC) (Vesty et al., 2018). Fungi in the oral wash of patients with HNSCC were further explored by Shay et al. (2020). They found reduced fungal evenness and richness in the HNSCC oral wash compared to healthy controls. Notably, specific strains of C. albicans were over- and under-represented, while Schizophyllum commune was depleted in oral wash samples from HNSCC patients (Figure 1A). S. commune is known to produce the polysaccharide compound, schizophyllan (Sung et al., 2018), which has anti-tumor properties in vitro and shows promise for the treatment of cancers, including HNSCC (Kimura et al., 1994; Mansour et al., 2012; Sung et al., 2018).

To ensure a relevant correlation with carcinogenesis, deep tissue biopsies are needed instead of saliva or surface swabs. Mukherjee et al. (2017) first observed that fungal richness was remarkably lower in OSCC (mobile) of tongue (OMTC) compared to the adjacent non-tumor tissues (Figure 1A). Notably, they also found a reduced abundance of Emericella in tumor tissues. In vitro studies have shown that Emericella exposure leads to increased p53 expression in colon cancer cell lines, which exerts anti-cancer effects (Mohamed, 2012). Therefore, the reduced abundance of this genus may induce decreased p53 expression, resulting in an oral cancer phenotype. Simultaneously, Perera et al. (2017) explored fungal differences in patients with OSCC and benign intra-oral fibro-epithelial polyps (FEPs). The diversity analysis was consistent with the above study, in patients with OSSC having significantly lower fungal evenness and richness than patients with FEP. Furthermore, compared to FEP populations, an overgrowth of C. albicans was detected in the OSCC cohort (Perera et al., 2017; Figure 2A). Interestingly, C. albicans was recently found to accelerate OSCC progression in vitro by increasing the synthesis of matrix metalloproteinases, oncometabolites, promoting protumor signaling pathways, and the upregulation of prognostic marker genes associated with metastatic events (Vadovics et al., 2022). Thus, C. albicans can promote the malignant progression of HNC. Intervention with C. albicans might serve as a potential therapeutic route for HNC.

Esophageal cancer (EC) impacts more than 450,000 people worldwide and has the sixth highest mortality rate of all cancers (Sung et al., 2021). Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are two main subtypes of EC, among which ESCC accounts for 90% of EC cases worldwide (Rustgi and El-Serag, 2014). The role of fungi in EC has not been extensively explored. However, some studies have suggested that specific fungal species may be involved in patients with ESCC having autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (Rautemaa et al., 2007; Zhu et al., 2017). APECED is a T-cell-driven autoimmune disease caused by mutations in the autoimmune regulator gene that induces defective T-cell central tolerance that hampers the elimination of T-lymphocytes responsive to host cells (Mathis and Benoist, 2009; Xing and Hogquist, 2012). Diminished or defective central tolerance makes patients with APECED more susceptible to developing chronic fungal infections and ESCC (Rautemaa et al., 2007; Manley et al., 2011). Rautemaa et al. (2007) assessed cancer risk in 92 patients with APECED and found that six out of the 92 patients had OSCC or ESCC. Five of these six patients had a history of oral candidiasis. Recently, Zhu et al. (2017) found that the nuclear factor, NF-κB inhibitor kinase alpha [Ikkα, plays a crucial role in forming and maintaining skin homeostasis (Hu et al., 1999; Liu et al., 2008) and functions as a tumor suppressor in the skin (Xia et al., 2010)] of knock-in mice developed phenotypes reminiscent of APECED, including impaired central tolerance, autoreactive T cells, chronic fungal infections, and ESCC. They also demonstrated that autoreactive CD4⁺ T cells permitted fungal infections, incited tissue injury, and inflammation. Antifungal treatment or depletion of autoreactive CD4⁺ T cells inhibited ESCC progression, whereas oral administration of Cladosporium cladosporioides promoted ESCC development (Zhu et al., 2017). The authors also revealed similarities between the hallmarks of ESCC from both patients who do not have APECED and Ikkα knockout mice (Zhu et al., 2017). Therefore, chronic fungal infections might promote ESCC, and antifungal therapy might be a potential candidate for the effective prevention and treatment of ESCC.

Gastric cancer (GC) is a highly fatal disease with the fifth-highest incidence and fourth highest mortality rate globally (Sung et al., 2021). Most cases are of the intestinal type of non-cardia GC, which often progresses histologically from atrophic gastritis (AG) to intestinal metaplasia and eventually to GC (Park and Kim, 2015). It is known that Helicobacter pylori (H. pylori) infection is the leading risk factor for this histological alteration, which causes inflammation of the gastric mucosa and disruption of the associated hydrochloric acid-secreting glands, leading to AG (Amieva and Peek, 2016). AG is a chronic inflammatory, hypochloremic state that may induce GC. Although H. pylori infection is known to contribute to this cascade, only about 1–3% of infected individuals subsequently develop GC (Peek and Crabtree, 2006; Stewart et al., 2020), suggesting that the presence of other components plays a crucial role in developing GC. The mycobiota were not involved in the carcinogenesis of GC, until recently. Zhong et al. (2021) analyzed the mycobiome of cancer lesions and adjacent non-cancerous tissues from 45 patients with GC. They found that there was a mycobiome disorder in GC tissues compared to paraneoplastic tissues, characterized by altered fungal composition and ecology (Figure 1B). Specifically, compared to the adjacent tissues, the alpha diversity of the mycobiome was significantly reduced in the GC tissues. The principal component analysis also revealed separate clusters between GC and adjacent tissues. More notably, they found that C. albicans was significantly elevated in GC tissues and could be used as a fungal biomarker for GC (Zhong et al., 2021). C. albicans might be involved in the pathogenesis of GC by reducing the diversity and abundance of fungi in the stomach (Zhong et al., 2021). Besides, Zhong et al. (2021) further acquired 10 healthy samples, and found no significant differences between healthy individuals and adjacent non-cancerous tissues.

Another study was not entirely consistent with these results, as it found no significant difference in alpha and beta diversity between the GC and the matched para-GC groups. However, the results also indicated that compared to gastric tissue from healthy populations, GC tissue had significantly lower alpha diversity of fungi, and the GC group also formed a relatively well-separated fungal flora (Yang et al., 2022). Furthermore, fungal dysbiosis was reflected by a higher proportion of opportunistic fungi, such as Cutaneotrichosporon and Malassezia in patients with GC compared to healthy controls (Yang et al., 2022; Figure 1B). The receiver operating characteristic (ROC) curves showed great diagnostic potential in distinguishing GC and healthy controls, including Cystobasidium, Cutaneotrichosporon, Apiotrichum, Simplicillium, Lecanactis, Rhizopus, Rhodotorula, Exophiala, and Sarocladium (Yang et al., 2022). Similar to the above study by Yang et al. (2022), Zhang et al. (2022) discovered no significant difference in fungal diversity between tumor and paracancerous tissues. Furthermore, they demonstrated that Solicoccozyma and Solicoccozyma aeria were significantly enriched in the tumor tissue (Figures 1B, 2B). In particular, the abundance of these two taxa was significantly higher in patients with GC at stage I or no nerve invasion than in patients with GC at stage II-IV or nerve invasion (Zhang et al., 2022).

According to Sung et al. (2021) CRC is the second most common contributor to cancer death (Sung et al., 2021). Recently, the CRC incidence rate has increased among young adults, and younger CRC patients present with more advanced disease, significantly reducing the quality of life of survivors and increasing the socioeconomic burden (Virostko et al., 2019). More than 80% of sporadic CRC cases are caused by colorectal adenomas (Jass, 2007; Ullman and Itzkowitz, 2011). Colorectal adenomas are classified as advanced or non-advanced (Davila et al., 2006). Advanced adenomas can further progress to carcinoma. With research progression, the link between fecal or mucosal mycobiota, colorectal adenomas, and CRC has received significant attention.

Primary liver cancer is the sixth most common cancer and the third major cause of cancer-related mortality globally, with hepatocellular carcinoma (HCC) comprising 75–85% of cases (Sung et al., 2021). Recently, a study showed significantly lower alpha diversity in patients with HCC than in patients with cirrhotic patients using ITS sequencing on stool samples from 11 cirrhotic patients and 17 HCC patients (Figure 2D; Liu Z. et al., 2022). The results of principal coordinates analysis revealed aggregation in patients with HCC and cirrhosis, respectively. More importantly, it was found that C. albicans was significantly enriched in the patients with HCC. The gavage of C. albicans in the wild-type mice with HCC increased the tumor size and weight (Liu Z. et al., 2022). Remarkably, the colonization of C. albicans did not affect tumor growth in nucleotide oligomerization domain-like receptor family pyrin domain containing 6 (NLRP6) knockout mice (Liu Z. et al., 2022). Thus, intestinal C. albicans could promote hepatocarcinogenesis through upregulation of NLRP6.

Pancreatic cancer is a highly malignant tumor with a 5-year survival rate of only 9% and is known as the “king of cancers” in oncology (Sung et al., 2021). This poor survival rate is due to factors, such as non-specific symptoms, lack of early diagnostic markers, aggressive tumor biology, and resistance to most currently available treatments. There is an urgent need for new prevention, screening, and treatment methods (Giovannetti et al., 2017). Recently, Aykut et al. (2019) pioneered the discovery that fungi can migrate from the intestinal lumen to the pancreas and those pathogenic fungi can promote pancreatic ductal adenocarcinoma (PDA) by activating the mannose-binding lectin (MBL)-complement-3 (C3) pathway. Specifically, PDA tumors display an approximately 3,000-fold increase in fungi compared to normal pancreatic tissue in both human and mouse models. The composition of fungi in PDA tumors was distinct from that of the intestine or normal pancreas. More strikingly, in mice and humans, the mycobiome infiltrating the PDA tumors was significantly enriched in Malassezia (Figure 1D). In contrast, benign pancreatic inflammation did not increase fungal infiltration of the pancreas (Aykut et al., 2019). To determine the effect of mycobiome dysbiosis on the progression of PDA, the investigators fed amphotericin B orally to slowly progressing and aggressive models of PDA to ablate their mycobiome, and the results showed that tumor growth was significantly inhibited in both models (Aykut et al., 2019). For patients with PDA, gemcitabine is still among the most widely prescribed drugs, but the response to this treatment is extremely poor (Meijer et al., 2019). Interestingly, the reduction of fungi by antifungal agents enhanced the effect of gemcitabine. However, anti-fungal treatment combined with gemcitabine did not prevent germ-free mouse tumor growth (Aykut et al., 2019). Surprisingly, the repopulation with a Malassezia (but not in Candida sp. Saccharomyces cerevisiae, or Aspergillus sp.) accelerated oncogenesis. Finally, it was observed that the MBL binding to glycans of the fungal wall to activate the complement cascade reaction was required for carcinogenic progression (Aykut et al., 2019). As we know, complement activation has many roles, including stimulating cell growth, survival, and migration, all of which are factors that promote tumor growth (Mamidi et al., 2017; Kochanek et al., 2018; Okrój and Potempa, 2018).

Another recent and important study found that intra-tumoral fungi (Malassezia globosa or Alternaria alternata) enhanced PDA cancer cell secretion of IL-33 by Dectin-1-mediated activation of the src proto-oncogene, non-receptor tyrosine kinase (Src)-spleen tyrosine kinase (Syk)-caspase recruitment domain-containing protein 9 (CARD9)-NF-κB pathway (Alam et al., 2022). The secreted IL-33 recruited and activated Th2 and innate lymphoid cells 2 (ILC2) in the tumor microenvironment (TME), which stimulated tumor growth by secreting pro-tumor cytokines, such as IL-4, IL-5, and IL-13 (Chevalier et al., 2017; Alam et al., 2022). Correspondingly, amphotericin B treatment or IL-33 deficiency significantly reduced tumor burden, improved survival, and decreased tumor-infiltrating ILC2 cells and Th2 cells (Alam et al., 2022). Therefore, it is likely that altering the mycobiome by targeting specific populations could help ameliorate PDA, and anti-fungal treatment might appear to be an attractive therapeutic option for PDA. Alternatively, treatments targeting the immune components, such as MBL and IL-33 that control fungal infections could also provide a promising way to fight this deadly cancer.

Melanoma is an aggressive malignancy caused by the uncontrolled proliferation of abnormal melanocytes. The progress of melanoma is rapid, and its prognosis is very poor, with a 5-year survival rate of 20% (Long et al., 2016; Hamid et al., 2019). The composition of the gut microbiome is associated with the prognosis and evolution of advanced melanoma and is considered a biomarker for immune checkpoint therapy (Gopalakrishnan et al., 2018; Mohiuddin et al., 2021). Recently, the intestinal fungal composition of melanoma patients was investigated for the first time by Vitali et al. (2021). They found significantly higher fungal richness in melanoma patients, and Saccharomycetales sp. was enriched in patients with melanoma compared to healthy controls (Figure 2E). Moreover, Malasseziales sp. and Malassezia globosa were significantly enriched in invasive melanoma compared to in situ melanoma (Vitali et al., 2021). Further research also found that the gut fungal profile may be relevant to melanoma regression. Regression involves T lymphocytes recognizing specific melanoma antigens that can destroy melanoma cells, induce progressive (partial or complete) tumor disappearance, and replace them with immune/fibrotic infiltration (Aung et al., 2017). However, its prognostic role remains controversial as the occurrence of immune/fibrotic infiltrates may cause an underestimation of Breslow thickness (Aung et al., 2017; Cartron et al., 2021).

Breast cancer surpassed lung cancer as the most common cancer worldwide in 2020, accounting for 11.7% of all cancer cases, and it is the fifth most frequent cause of death worldwide (Sung et al., 2021). Over the past decades, considerable progress has been made in diagnosing and treating breast cancer. However, more research is needed to improve the prognosis and overcome the resistance to advanced breast cancer (Ginsburg et al., 2017). Shiao et al. (2021) discovered the modulation of tumor immunity by fecal mycobiota during breast cancer radiotherapy, providing a new idea to improve the clinical efficacy of radiotherapy. They administered antifungal (AF) drugs orally to mice with breast cancer, which had a limited influence on bacterial levels, but reduced gut fungal levels. The results showed that AF combined with radiation therapy (RT) significantly inhibited tumor growth, promoted tumor cell death, and prolonged survival time in mice compared to RT alone (Shiao et al., 2021). Similar efficacy was found in the melanoma model (Shiao et al., 2021). Further examination of the changes in immune cells in tumor tissues showed that CD4⁺ T cells and CD206⁺F4/80⁺ immunosuppressive macrophages were decreased, while CD8⁺ anti-tumor T cells were increased in the AF combined with RT compared to RT alone, suggesting that gut fungi can modulate the tumor immune microenvironment by affecting macrophages and T cells (Shiao et al., 2021). Next, by supplementing C. albicans combined with RT in mice with breast cancer, the authors found that the tumor growth was faster, and the survival time was shorter than the RT-only treatment, and the ratio of PD-1⁺CD8⁺ T cells was significantly increased, indicating a more immunosuppressive TME allowing for tumor growth. All of these effects were reversed when C. albicans were inhibited with AF (Shiao et al., 2021). Finally, it was discovered that elevated intra-tumoral Dectin-1 expression was negatively related to the survival of patients with breast cancer and was required for the effect of commensal fungi’ on mouse models with RT (Shiao et al., 2021). Previous studies have also reported that C. albicans infection can increase Treg numbers in the TME and splenocytes and promote breast cancer growth (Ahmadi et al., 2019). Considering that most patients with cancer are usually on antibiotics, the knowledge that the overgrowth of specific fungi may lead to the creation of an immunosuppressive TME, which reduces the efficiency of anti-tumor therapy, could be very relevant (Riquelme and McAllister, 2021). Thus, intestinal fungi may be an effective target for improving the efficacy of cancer therapy.

Cancer cachexia (CC) is a metabolic syndrome related to several underlying diseases, such as cancer and chronic kidney disease, among many others (Fearon et al., 2011). It is characterized by a decrease in muscle mass, the depletion of body fat, and widespread chronic inflammation (Fearon et al., 2011). Its prevalence in patients with different types of cancer significantly reduces their life quality and expectancy (Bruera and Hui, 2012). Recently, Jabes et al. (2020) explored the alterations of gut fungi in CC mice inducted by subcutaneous inoculation with Lewis lung carcinoma cells (a model widely employed for the study of CC) (Bennani-Baiti and Walsh, 2011). They found that there were sufficient differences in the composition of intestinal fungi to distinguish the CC mice and control mice by beta diversity analysis. Furthermore, linear discriminant analysis effect size (LEfSe) and real-time quantitative PCR showed a significantly higher abundance of Saccharomyces, Kazachstania, Saccharomyces cerevisiae, Malassezia, Malassezia dermatitis, and Malassezia japonica in the feces of CC mice, while the abundance of Rhizopus oryzae was significantly higher in the control mice (Figure 2F; Jabes et al., 2020). Previous studies have shown that R. oryzae can produce large amounts of various antioxidants and organic acids, including gallic acid (Londoño-Hernández et al., 2017). Interestingly, an extract of oil palm phenolics, containing 1,500 ppm gallic acid equivalent, has been shown to suppress tumorigenesis, by mediating G1/S phase cell cycle arrest, delaying inflammatory responses, and attenuating CC symptoms in tumor-bearing mice (Leow et al., 2013). Gallic acid has also been found to increase glucose tolerance and triglyceride concentrations in obese mice (Leow et al., 2013), inhibit lipogenesis in humans, and counteract pro-inflammatory responses (Dludla et al., 2018). Thus, there is a disorder of the fecal mycobiome in CC, and R. oryzae might be a promising candidate probiotic that deserves further study. However, CC is triggered by different factors that influence the development and outcomes of the syndrome in different ways and might affect the alterations in the gut mycobiota, which needs further exploration.

Dectin-1, also known as the β-glucan receptor, is an emerging pattern recognition receptor encoded by C-type lectin domain family 7 member A (CLEC7A) (Huysamen and Brown, 2009; Mayer et al., 2017). β-glucans are the most common pathogen-associated molecular patterns (PAMPs) found in fungal cell walls that are recognized by Dectin-1. The expression of Dectin-1 has been predominantly observed in myeloid cells, including macrophages, dendritic cells (DCs), monocytes, and neutrophils (Brown and Crocker, 2016). The most widely known role of Dectin-1 is antifungal defense, as summarized in these reviews (Kimberg and Brown, 2008; Marakalala et al., 2011; Saijo and Iwakura, 2011). The critical role of Dectin-1 in immune defense provides a general reflection that its deficiency will increase the risk of infectious diseases (Kalia et al., 2021). Dectin-1 knockout mice significantly increase the fungal burden and low survival rates (Taylor et al., 2007).

Along with the concern about the carcinogenic role of fungi, the role of Dectin-1 in tumor development has also attracted the interest of scholars globally. Recently, several studies have demonstrated that Dectin-1 plays an extremely important role in the anti-tumor immune response (Figure 3). For example, Seifert et al. (2015) found that the expression level of Dectin-1 was highly upregulated in both liver fibrosis and HCC (highly expressed in DCs and macrophages, not in hepatocytes). Dectin-1 deficiency accelerated liver fibrosis and hepatocellular tumorigenesis (Seifert et al., 2015). Whereas Dectin-1 activation inhibited Toll-like receptor 4 (TLR4) signaling in hepatic inflammatory and stellate cells by attenuating the TLR4 and its co-receptor CD14 expression, thereby suppressing liver fibrosis and hepatocarcinogenesis (Figure 3A; Seifert et al., 2015). Chiba et al. (2014) indicated that Dectin-1 expression on DCs and macrophages was essential for the enhancement of NK-mediated killing of tumor cells that express high levels of N-glycan structures. Dectin-1 recognition of N-glycan led to the activation of the interferon regulatory factor 5 (IRF5) and downstream genes, such as INAM (termed as a family with sequence similarity 26 member F), inducing the full-blown tumoricidal activity of natural killer (NK) cells (Figure 3A; Chiba et al., 2014). Similarly, a recent study found that IL-13-mediated Dectin-1 and mannose receptor (MR) overexpression promoted the anti-tumor activity of macrophage by recognizing sialic acid-specific glycan structures on the tumor surface. Specifically, Dectin-1 and MR enhanced the cytotoxic function of macrophages through the activation of downstream Syk-neutrophil cytosolic factor 1 (P47^phox) signaling and arachidonic acid (AA)-the 12- and 15-hydroxyeicosatrienoic acids (HETE)-peroxisome proliferator-activated receptor gamma (PPARγ) axis, thereby inhibiting the progression of T-cell lymphoma, ovarian adenocarcinoma, and breast adenocarcinoma (Figure 3A; Alaeddine et al., 2019).

In addition, Dectin-1 also plays an important role in regulating the anti-tumor effects of DCs. For example, tumor-associated DCs are also activated by Dectin-1, which simultaneously blocks Th2 cells and induces CD103⁺CD8⁺ mucosal T-cell differentiation to eliminate pre-existing breast cancers (Figure 3B; Wu et al., 2014). Th9 cells have been shown to mediate effective anti-tumor effects in vivo (Purwar et al., 2012; Schanz et al., 2021). Dectin-1 activated DCs triggered effective anti-tumor immunity by inducing Th9 cells (Figure 3B; Zhao et al., 2016). Specifically, Dectin-1 activated Syk/raf-1 proto-oncogene, serine/threonine kinase (Raf1)-NF-κB signaling pathways in DCs, leading to increased tumor necrosis factor ligand superfamily member 15 (TNFSF15) and tumor necrosis factor ligand superfamily member 4 (TNFSF4) expression, which in turn was instrumental in triggering the differentiation of naive CD4⁺ T cells to Th9 cells (Figure 3B; Zhao et al., 2016). Wang D. et al. (2018) also found that Dectin-1 activation enhanced interferon regulatory factor 4 (IRF4) expression via the Syk/Raf1-NF-κB pathways, which consequently upregulated IL-33 expression in DCs. The blockade of IL-33 can inhibit Dectin-1-activated DC-induced Th9 cell differentiation, and the complement of IL-33 further promotes Th1 cell and Th9 cell priming and antitumor efficacy (Figure 3B; Chen et al., 2018).

However, in a contrasting role, some studies have shown that Dectin-1 is an oncogenic marker (Xia et al., 2016; Daley et al., 2017). For example, Xia et al. (2016) found that Dectin-1 was mainly expressed in the tumor cells and that high Dectin-1 expression was an independent predictor of poor clinical outcomes in patients with clear cell renal cell carcinoma (ccRCC). Daley et al. (2017) also revealed upregulated Dectin-1 expression in the tumor and peritumoral inflammatory compartment in PDA, and Dectin-1 signaling accelerated PDA progression. Interestingly, activation or knockdown of Dectin-1 did not affect the proliferative capacity of transformed pancreatic epithelial cells, and the deletion of Dectin-1 in the extra-epithelial compartment was protective against tumorigenesis (Daley et al., 2017). Mechanistic studies revealed that Dectin-1 ligated the lectin Galectin-9 in the PDA TME, leading to tolerogenic macrophage programming and adaptive immunosuppression. Following the disruption of the Dectin-1-Galectin-9 axis, CD4⁺ and CD8⁺ T cells were reprogrammed as indispensable mediators of anti-tumor immunity (Daley et al., 2017). Additionally, it was demonstrated that increased fungal abundance and the resulting aberrant Dectin-1 signaling might play a role in accelerated oral carcinogenesis in aged mice (Bhaskaran et al., 2021). Dectin-1-deficient mice showed reduced infiltration of Tregs and myeloid-derived suppressor cells (MDSCs) in the tongue, and slower tumor progression (Bhaskaran et al., 2021).

All of these factors suggest an important but uncertain role of Dectin-1 in cancer, an essential controversy that needs to be thoroughly addressed. Furthermore, the impact of human fungal microbiota on the function of Dectin-1 in tumors is not well studied, and further research is urgently needed.

Dectin-2, encoded by C-type lectin domain family 6 member A (CLEC6A), is generally expressed in myeloid cells, including various subtypes of DCs and macrophages upon activation (Taylor et al., 2005; Robinson et al., 2009). Dectin-2 can bind with α-mannan or zymosan, the key components of C. albicans, Cryptococcus neoformans, and others. Dectin-3, also known as Macrophage C-Type Lectin (MCL), encoded by C-type lectin domain family 4 member D (CLEC4D), has a similar structure as Dectin-2 (Ariizumi et al., 2000). Dectin-3 is expressed in peripheral blood neutrophils, monocytes, and various subsets of DCs (Graham et al., 2012). Dectin-3 primarily recognizes trehalose 6, 6-dimycolate (TDM) and α-mannan expressed on the hyphal form of the fungi cell wall (Arce et al., 2004; Graham et al., 2012). Dectin-3 can form a heterodimeric complex with Dectin-2 to recognize α-mannan, which has a higher affinity than homodimers of Dectin-2 or Dectin-3 for sensing C. albicans infections and induces a potent activation of NF-κB-dependent anti-fungal immune responses (Zhu et al., 2013).

Recently, Dectin-2 and Dectin-3 in the anti-tumor response have also been studied. Dectin-3 expression was significantly increased in patients with a low fungal burden than in patients with a high fungal burden, indicating the function of Dectin-3 on the host anti-fungal immunity (Zhu et al., 2021). Subsequently, the impact of Dectin-3 on fungal dysbiosis and tumor progression was estimated. Dectin-3 deficiency can promote CAC occurrence, and contribute to the increased fecal fungal burden (Zhu et al., 2021). ITS sequencing showed that the abundance of C. albicans was significantly higher in mice lacking the C-type lectin Dectin-3. Further research found the feces of Dectin-3 knockout tumor-bearing mice, as well as C. albicans, promote the malignant process of CAC, and anti-fungal treatment (fluconazole) effectively alleviates the tumor load of Dectin-3 knockout mice (Zhu et al., 2021). In vitro and in vivo experiments demonstrated that Dectin-3 deletion led to impaired clearance of C. albicans by macrophages. Increased C. albicans induced the upregulation of glycolysis levels in macrophages via the HIF-1 pathway, triggering an increased secretion of IL-7 from macrophages. In turn, IL-7 could induce IL-22 production in intestinal intrinsic lymphocytes 3, which ultimately promotes the proliferation of IECs and the progression of CAC (Zhu et al., 2021).

Kimura et al. (2016) also found that Dectin-2 was expressed on resident liver macrophages (Kupffer cells) and played a key role in inhibiting liver metastasis by enhancing the phagocytic activity of macrophages toward colon carcinoma and melanoma cells. Interestingly, this Dectin-2-mediated activity was specific to Kupffer cells, as neither bone marrow-derived macrophages (BMDMs) nor alveolar macrophages engulfed the colon carcinoma in a Dectin-2-dependent manner (Kimura et al., 2016). Furthermore, wild-type mice were treated with antibacterial or anti-fungal antibiotics, but no significant increase was found in colon carcinoma metastasis in the liver, suggesting that Dectin-2 in Kupffer cells acts independently of microbiota on cancer cells (Kimura et al., 2016). Similar to Dectin-2, Dectin-3 also mediates the uptake of colon cancer cells by Kupffer cells and inhibits liver metastasis. Notably, Dectin-1 is also involved in metastatic immune responses in the liver, independent of the phagocytotic activity of Kupffer cells against colon carcinoma cells. Instead, Dectin-1-induced anti-tumor killing was mediated by hepatic non-parenchymal cells (NPCs) (Kimura et al., 2016). As we know, NK cells are primarily responsible for the cytotoxic activity of liver NPCs (Cohen et al., 1990), which is consistent with previous findings (Chiba et al., 2014) that Dectin-1 signaling in DCs and macrophages enhances NK cell-mediated tumoricidal activity.

Current evidence suggests that Dectin-2 and Dectin-3 play an anti-tumor role. Manipulating their anti-tumor response to control CRC formation and liver metastasis is a promising therapeutic approach.

Mincle, encoded by C-type lectin domain family 4 member E (CLEC4E), also known as Macrophage-Inducible C-Type Lectin, is mainly expressed on professional antigen-presenting cells (APCs), such as macrophages, DCs, B cells, and neutrophils (Yamasaki et al., 2009). Mincle plays a crucial role in anti-fungal immunity, recognizing pathogenic fungi, such as Malassezia, C. albicans, and Fonsecaea pedrosoi (Wells et al., 2008; Yamasaki et al., 2009; Sousa Mda et al., 2011).

Unlike Dectin-2 and Dectin-3, recent studies have revealed a pro-cancer role for Mincle in the progression of various cancers. The seminal study by Roperto et al. (2015) showed that Mincle expression was increased in urothelial tumors of the urinary bladder of cattle compared to healthy individuals. As we know, the anti-tuberculosis vaccine strain, Bacillus Calmette-Guérin (BCG) is used clinically as an immunotherapy against bladder cancer (Gandhi et al., 2013). The immune mechanism behind this is not well understood (Redelman-Sidi et al., 2014), but BCG-derived TDM might be involved, as Mincle is also a key receptor for TDM (Ishikawa et al., 2009). Li et al. (2020) demonstrated that Mincle was highly expressed in tumor-associated macrophages (TAMs) and significantly associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). The secretome of cancer cells induced Mincle expression in TAMs, and Mincle promoted M2 polarization of TAMs by suppressing the M1 phenotype, thus promoting cancer progression in invasive lung cancer and melanoma. Mechanistic studies revealed that Mincle promoted TAM-mediated pro-tumoral activities via the Syk-NF-κB-IL-6 inflammatory pathway (Li et al., 2020). IL-6 is a cancer promoter (Feng et al., 2018), produced mainly by TAMs (Lv et al., 2016), and is thought to be a poor prognostic factor for various cancers (Tang et al., 2018a,b).

Furthermore, Seifert et al. (2016) reported that in PDA, SAP130 (a subunit of the histone deacetylase complex) expression was evident in both epithelial and inflammatory cells. In contrast, Mincle was only highly expressed in inflammatory cells (MDSCs, DCs, and macrophages). Ligation of Mincle by SAP130 increased the infiltration of M2 macrophages and MDSCs and inhibited cytotoxic T-cell function, which induced pancreatic tumorigenesis. Mincle deletion markedly suppressed pancreatic tumorigenesis by enhancing the immunogenicity of TME (Seifert et al., 2016). For treating the carcinogenic effects of Mincle, Xue et al. (2021) successfully developed a novel virus-free gene therapy, USMB-shMincle, by combining RNA interference technology with an ultrasound-microbubble (USMB)-mediated delivery system, and demonstrated its anti-cancer efficiency and safety in two xenograft nude mouse models of human melanoma and lung cancer. USMB-shMincle significantly enhanced the anti-cancer M1 phenotype of TAMs by blocking the protumoral Mincle-Syk-NF-κB-IL-6 signaling. Therefore, Mincle may represent a new target for treating aggressive cancers.

Caspase recruitment domain-containing protein 9 is an intracellular adapter protein from the CARD protein family and is identified for its selective binding to the CARD domain of BCL10 (Bertin et al., 2000). CARD9 is selectively expressed in myeloid-derived innate immune cells, especially in macrophages and dendritic cells (Hsu et al., 2007; Roth and Ruland, 2013), where it operates as a central integrator of the innate and adaptive immune system. It can integrate signals from the CLR and plays a very important role downstream of the anti-fungal Dectin-1, Dectin-2, Dectin-3, and Mincle (Gross et al., 2006; Robinson et al., 2009; Shenderov et al., 2013). Recent studies have confirmed that CARD9 may play a crucial role in a variety of cancers, particularly CRC and lung cancer.