The review, authored by Wu Yinhang, Han Shuwen, Zhuang Jing, and Feng Min from institutions including the First Affiliated Hospital of Huzhou University and Tarim University, synthesizes a rapidly growing body of evidence showing that the gut mycobiome undergoes profound and measurable reorganization during colorectal cancer development. Metagenomic studies consistently find that patients with colorectal cancer carry a lower fungal alpha-diversity than healthy individuals, a hallmark of ecological collapse within this community. More striking is the direction of that collapse: pathogenic species such as Malassezia globosa and Aspergillus rambellii become enriched, while protective commensal fungi, including members of the Saccharomycetes and Pneumocystidomycetes classes, dwindle. A meta-analysis drawing on seven studies and 1,329 fecal metagenomic datasets pinpointed six fungal species significantly enriched in patients, among them Aspergillus rambellii, Cordyceps sp. RAO-2017, Erysiphe pulchra, and Phytophthora capsici. The researchers emphasize that this is not a random disturbance but a stage-specific evolutionary pattern, a kind of fungal signature that deepens as healthy tissue progresses through adenoma and into carcinoma.

The mechanistic story begins with toxins. Candida albicans, the most intensively studied fungal pathogen in this context, secretes candidalysin, a small peptide toxin that punches holes in epithelial cell membranes. According to the review, candidalysin interacts directly with the host protein cyclin H, inducing DNA double-strand breaks while simultaneously activating CDK kinases that suppress DNA damage repair, a double hit that leaves intestinal mucosal cells genomically compromised. The toxin also triggers a cascade of cellular stress responses: reactive oxygen species generation, ATP depletion, mitochondrial dysfunction, and cytochrome C release, along with activation of the epidermal growth factor receptor pathway. Beyond candidalysin, several Candida species, including C. albicans and C. tropicalis, can metabolize ethanol into acetaldehyde and generate nitrosamine carcinogens. Acetaldehyde drives oxidative stress, raises intracellular calcium, activates calcium-calmodulin-dependent protein kinase II, and phosphorylates Drp1, pushing mitochondria into abnormal fission and dysfunction. Excessive reactive oxygen species then compound genomic instability, while acetaldehyde simultaneously dismantles the tight junctions that hold the intestinal barrier together.

Fungi also reshape the immune microenvironment in ways that can either restrain or accelerate cancer, often through pattern recognition receptors. C-type lectin receptors such as Dectin-1 and Dectin-2, expressed on dendritic cells, macrophages, and neutrophils, sense fungal cell wall components like beta-glucans and high-mannose carbohydrates, signaling through the Syk-CARD9 pathway to activate NF-kappaB and assemble inflammasomes. In healthy states this axis suppresses colitis and colorectal cancer, promoting interleukin-18 release that enhances epithelial repair and activates CD8-positive T cells to produce interferon-gamma. But the balance is precarious. In mouse models of colitis-associated cancer, CARD9-deficient animals show attenuated inflammation but paradoxical dynamics in fungal load, while deletion of Dectin-3 predisposes to cancer with markedly increased pathogenic fungal colonization. The review also describes a newly identified c-Cbl/RelB axis, in which fungal alpha-mannans activate the E3 ubiquitin ligase c-Cbl through Dectin-2 and Dectin-3, promoting degradation of the NF-kappaB family member RelB and altering susceptibility to colitis. Meanwhile, pathogenic fungi expand myeloid-derived suppressor cells, which impair CD8-positive T cell function and create an immunosuppressive milieu favorable for tumor growth and metastasis.

The Th17 axis illustrates what the authors call the double-edged sword of fungal immunity. Candida albicans can drive robust Th17 polarization, with interleukin-17 signaling through its receptor to activate MAPK and NF-kappaB pathways, stimulate STAT3-dependent tumor growth, and provoke tumor cells to produce reactive oxygen species and hydrogen peroxide that accelerate tumor growth. Interleukin-22, secreted by gamma-delta T cells and group 3 innate lymphoid cells, further complicates the picture: it induces oncostatin M receptor expression in intestinal epithelial cells, synergistically activating STAT3 to propel colitis-associated cancer, and tumor-associated IL-22 levels correlate strongly with fungal burden. Yet in late-stage disease, interleukin-17 receptor A signaling may actually foster antifungal antitumor immunity by modulating macrophages, and treating mice with the antifungal amphotericin B worsened tumor aggressiveness in some models. On the protective side, a commensal strain of Candida tropicalis has been shown to elevate IL-17A and IL-22 through Th17 and ILC3 activation, enhance epithelial proliferation, reduce intestinal permeability, and modulate vitamin B3 metabolism to strengthen the mucosal barrier.

Perhaps the most conceptually ambitious section of the review concerns cross-kingdom interactions, the ecological negotiation between fungi and bacteria that appears to tip decisively in cancer. Metagenomic analyses show that patients with colorectal cancer display predominantly positive fungal-bacterial correlations, in contrast to the competitive balance seen in health. The interactions take three forms. In competition, commensal anaerobic bacteria such as Clostridium clusters IV and XIVa and Bacteroides suppress Candida albicans colonization by upregulating hypoxia-inducible factor-1 alpha and boosting production of the antimicrobial peptide LL-37, while Lactobacillus rhamnosus starves the fungus of preferred nutrients and remodels the metabolic environment. In mutualism, fungi and bacteria co-aggregate into polymicrobial biofilms, as when Candida tropicalis forms mixed films with E. coli or Streptococcus mutans, complete with abundant fungal hyphae and even bacterial-fungal cell fusion, which strengthen resistance to host defenses and antibiotics while continuously releasing pro-inflammatory factors and carcinogenic metabolites. In a compelling experimental demonstration, colistin treatment combined with either Saccharomyces boulardii or Candida albicans attenuated both the anti-colitic and pro-colitic effects of those fungi, and reintroducing E. coli restored them, proving that Enterobacteriaceae are essential facilitators of fungal activity in the gut.

These signatures are not merely descriptive; they carry clinical weight. Elevated tumor levels of Candida species correlate with pro-inflammatory tumor gene activity, enhanced cancer cell adhesion, advanced stage, distant metastasis, and poor outcomes. Candida albicans secretes aspartic proteases that degrade the extracellular matrix, promoting liver metastasis. Intratumoral fungal communities grow progressively more heterogeneous across the adenoma-carcinoma sequence, and that heterogeneity tracks with KRAS mutations and microsatellite instability, two of the most important molecular features in colorectal carcinogenesis. Fungal biomarkers such as Malassezia and Aspergillus may therefore serve as non-invasive predictors of KRAS status and MSI, and multi-kingdom models combining fungal and bacterial markers show enhanced sensitivity for early detection over bacteria alone. Notably, gut fungi outperform bacteria in predicting response to immune checkpoint inhibitors, suggesting that a patient’s mycobiome could one day guide immunotherapy decisions.

The therapeutic implications run in several directions at once. Old drugs are finding new jobs: terbinafine, a squalene epoxidase inhibitor, synergizes with oxaliplatin and 5-fluorouracil to inhibit colorectal cancer growth, reduces fungal load, decreases myeloid-derived suppressor cell infiltration, restores CD8-positive T cell function, and enhances response to anti-PD-1 therapy in resistant models, apparently by inhibiting glucose-6-phosphate dehydrogenase, lowering the NADP/NADPH ratio, and starving cancer cells of deoxyribonucleotides. Itraconazole suppresses Wnt signaling and eliminates dormant intestinal cancer cells. Lifestyle-based interventions matter too: Mediterranean-style diets, high-fiber foods, and polyphenol-rich nutrients promote beneficial fungi and suppress Candida and Aspergillus species while feeding short-chain fatty acid production, whereas high-fat, high-sugar, and high-protein diets push the community in the opposite direction. The probiotic Saccharomyces boulardii, the best-studied fungal probiotic, repairs epithelial tight junctions, eases colonic inflammation, and remodels bacterial communities by lowering the Firmicutes to Bacteroidetes ratio and reducing cancer-associated bacteria.

The most futuristic proposals involve engineered fungi as living medicines. One system, dubbed SC@CS@5-FC, uses an orally administered engineered Saccharomyces cerevisiae that accumulates in tumor tissue, responds to overexpressed hyaluronidase by releasing the prodrug 5-fluorocytosine, and converts it intracellularly into 5-fluorouracil via yeast-encoded cytosine deaminase, generating chemotherapy in situ while beta-glucans and zinc-chitosan nanoparticles activate dendritic cells. A second platform, Sb_haPD-1, embeds a gene for miniaturized anti-PD-1 into Saccharomyces boulardii, which secretes the checkpoint inhibitor locally in the gut, reversing immune suppression and shrinking tumors in APC-min mice with reduced regulatory T cells and expanded CD4-positive TNF-alpha-positive T cells. Fungal metabolites are also being mined as drugs: bipoterprides A through L, isolated from the endophytic fungus Bipolaris victoriae, inhibit the colorectal cancer target human dCTP pyrophosphatase 1, inducing cell cycle arrest, apoptosis, and autophagic death, with the lead compound showing potent antitumor activity without significant toxicity. Meanwhile, xylan-capecitabine nanoparticles raised tumor suppression rates in mice from 5.29 percent to 71.78 percent by boosting short-chain fatty acids, suppressing the NF-kappaB-IL-6-STAT3 axis, and recruiting CD8-positive T cells.

The authors are careful to flag the caveats. Direct causal evidence that fungal-bacterial interactions initiate colorectal cancer remains limited, safety profiles and manufacturing feasibility for engineered fungal delivery systems require rigorous testing, and the heterogeneity of mycobiota patterns across tumor subtypes, anatomical locations, and molecular backgrounds complicates any one-size-fits-all approach. Still, the trajectory of the field is unmistakable. What was once a barely explored 0.1 percent of the microbiome now offers a coherent framework spanning diagnostics, prognostics, drug repurposing, probiotics, and synthetic biology. As the review concludes, integrating multi-omics data with synthetic biology and advanced biomaterials could accelerate the translation of fungal science from dysbiosis descriptions into precision medicine for colorectal cancer, a shift that may redefine how the third most common cancer in the world is detected and treated.