Cancer and Fungus: How Fungi Impact Tumor Biology

Fungi are an often-overlooked component of the tumor microenvironment, yet emerging research suggests they may significantly influence cancer progression. These microorganisms impact immune system modulation and interact directly with tumor cells. While bacteria have long been studied in oncology, fungi are now gaining attention as contributors to disease development and treatment resistance.

Understanding fungal interactions with tumors could lead to new diagnostic and therapeutic approaches. Researchers are uncovering complex relationships between fungal species, mycotoxins, immune responses, and microbial ecosystems within tumors, offering deeper insights into cancer biology and its vulnerabilities.

Mycobiome Composition in Oncology

The fungal communities within tumors, collectively known as the mycobiome, vary across cancer types. Recent sequencing studies have shown that certain fungal species are more prevalent in specific malignancies, suggesting a non-random distribution influenced by tumor microenvironmental factors. A study published in Cell (2022) found Malassezia species enriched in pancreatic ductal adenocarcinoma, while Candida species were frequently detected in gastrointestinal and lung tumors. This suggests fungal colonization is shaped by tumor-specific metabolic and structural conditions.

Fungal presence within tumors is influenced by oxygen availability, nutrient gradients, and local tissue architecture. Hypoxic regions may favor anaerobic or facultative anaerobic fungi, while necrotic areas provide organic material that supports fungal persistence. A study in Nature Microbiology (2023) found fungal DNA and RNA signatures more abundant in tumors with disrupted vascularization, suggesting compromised blood flow creates ecological niches conducive to fungal survival.

Beyond their presence, tumor-associated fungi may contribute to disease progression through metabolic activity. Some species produce secondary metabolites that alter the tumor’s biochemical landscape, affecting cellular proliferation and survival. Aspergillus species, for example, produce gliotoxin, which interferes with cellular redox balance and promotes oxidative stress. Candida albicans secretes acetaldehyde, a carcinogen that induces DNA damage. These metabolic byproducts may not only impact tumor cells directly but also modify the surrounding microenvironment in ways that support malignancy.

Mycotoxins and Cellular Changes

Fungi associated with tumors produce mycotoxins, bioactive secondary metabolites that disrupt cellular function. These compounds contribute to genomic instability, altered signaling pathways, and metabolic shifts that facilitate tumor progression. Aflatoxins, produced by Aspergillus flavus and Aspergillus parasiticus, are well-documented carcinogens. Studies in The Lancet Oncology have linked chronic aflatoxin exposure to hepatocellular carcinoma, showing that aflatoxins form DNA adducts at codon 249 of the TP53 gene, leading to mutations that impair tumor suppression.

Beyond direct mutagenesis, mycotoxins influence tumor cell behavior by altering intracellular signaling. Ochratoxin A, produced by Penicillium and Aspergillus species, disrupts protein phosphatase activity, leading to dysregulated cell cycle control. Research published in Carcinogenesis found that ochratoxin A exposure in renal epithelial cells increased cyclin D1 expression while reducing tumor suppressor p21, promoting unchecked proliferation. Similarly, gliotoxin from Aspergillus fumigatus disrupts redox homeostasis by inhibiting thioredoxin reductase, increasing reactive oxygen species (ROS) levels, and fostering DNA damage and apoptotic resistance—hallmarks of aggressive tumors.

Fungal metabolites also drive metabolic reprogramming in tumor cells. Fumonisins, produced by Fusarium species, inhibit ceramide synthesis, a key process in sphingolipid homeostasis. A study in Nature Communications reported that fumonisin-induced ceramide depletion in colorectal cancer cells enhanced glycolytic activity, promoting the Warburg effect, which supports rapid proliferation under hypoxic conditions. This metabolic adaptation may also create a favorable environment for fungal persistence, reinforcing a feedback loop between tumor and fungal interactions.

Immune Response Pathways

Fungal components within tumors influence immune surveillance, shaping the balance between pro- and anti-tumor immune activity. Many fungi express molecular patterns that trigger innate immune receptors such as dectin-1, toll-like receptors (TLRs), and C-type lectin receptors, which are essential for fungal recognition. When tumor-associated macrophages and dendritic cells encounter fungal β-glucans, they activate signaling cascades that lead to cytokine secretion, particularly interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). While these inflammatory mediators enhance immune cell recruitment, chronic exposure may contribute to an immunosuppressive microenvironment by promoting myeloid-derived suppressor cell (MDSC) expansion, dampening cytotoxic T cell responses.

Fungal-derived mannans and chitin fragments influence adaptive immunity by skewing CD4+ T cell polarization, favoring regulatory T cell (Treg) expansion while suppressing anti-tumor Th1 and Th17 responses. This shift, observed in multiple malignancies, correlates with poorer prognosis due to suppressed effector T cell activity. Additionally, fungal antigens presented via major histocompatibility complex (MHC) class II molecules on dendritic cells can induce CD8+ T cell anergy, limiting effective anti-tumor responses.

Fungal metabolites also modulate immune pathways, affecting tumor progression and treatment response. Some fungi secrete compounds that interfere with immune checkpoint signaling. Gliotoxin from Aspergillus fumigatus inhibits NF-κB activation, impairing dendritic cell maturation and antigen presentation, ultimately weakening T cell priming and immune-mediated tumor clearance. Additionally, fungal-induced metabolic shifts, such as lactate accumulation in the tumor microenvironment, impair immune cell function by promoting an acidic milieu that inhibits T cell proliferation and cytokine production.

Colonization Patterns in Tumor Sites

Fungal distribution within tumors is shaped by structural and biochemical properties of malignant tissues. Tumor architecture, including vascular integrity, extracellular matrix composition, and necrotic regions, creates microenvironments that selectively favor fungal persistence. Hypoxic cores in solid tumors provide oxygen-deprived niches where certain fungi thrive. These areas also accumulate metabolic byproducts such as lactate and succinate, which may further support fungal colonization by serving as alternative carbon sources.

Fungal presence has been linked to specific histological features. In pancreatic adenocarcinoma, fungal cells have been observed in perivascular regions, where compromised blood flow likely facilitates their retention. Colorectal tumors often harbor fungi within mucin-rich pockets, possibly due to the adhesive properties of fungal cell walls interacting with mucus glycoproteins. Advanced imaging technologies, such as spatial transcriptomics and in situ hybridization, have revealed that certain fungal species are more prevalent in regions of tissue remodeling, where disrupted cell-cell junctions and increased permeability enhance fungal infiltration.

Interactions With Other Microbes

Fungi in tumors interact dynamically with bacterial and viral populations, shaping the microbiome in ways that influence cancer progression. These interactions can either enhance or suppress tumor growth, depending on the species involved and the biochemical exchanges taking place. Candida albicans, for example, engages in biofilm formation alongside pathogenic bacteria, creating a protective matrix that enhances microbial persistence and resistance to therapeutic agents. This structural cooperation shields tumor-associated microbes from immune clearance and antimicrobial treatment, prolonging their influence on local tissue dynamics.

Metabolic interactions between fungi and bacteria also alter the biochemical landscape of tumors. Some fungi produce metabolites that serve as substrates for bacterial fermentation, leading to the accumulation of pro-tumorigenic compounds. Aspergillus species generate ethanol as a metabolic byproduct, which certain gut bacteria convert into acetaldehyde, a carcinogen that induces DNA damage. Conversely, some bacterial communities suppress fungal overgrowth by secreting antifungal peptides or outcompeting fungi for essential nutrients. This competitive exclusion has been observed in colorectal cancer, where a balanced microbiome is associated with lower fungal burdens, suggesting microbial diversity influences fungal colonization patterns in tumors.