Unraveling the mycobiome's role in cancer

Background

A growing body of evidence indicates that the microbiome within the gut and tumors significantly influences cancer initiation, progression, and treatment response. Current research primarily focuses on bacteria, whilst the role of fungi is only now gaining attention.

The authors address key questions that have caused confusion and hindered clinical translation: (a) Why should we value the role of mycobiome in oncological research? (b) What will the relationship between fungi and bacteria be in cancer progression? (c) How will the fungi impact cancer? (d) Can we target fungi for development of intervention strategies in anticancer treatment? (e) Will the effort and investment pay back in mycobiome-driven cancer research?

Research progress

Despite their low abundance in tumor tissues (approximately 4%~13.3%), fungi exhibit widespread distribution, high signal activity, and type-specificity across multiple cancers, including lung, breast, colorectal, and pancreatic cancers. Through highly sensitive techniques such as ITS sequencing and single-cell sequencing, tumor-associated fungi including Candida, Malassezia, and Aspergillus have been identified. These fungi may promote tumour progression by activating immunosuppressive pathways (e.g., Dectin-1/CARD9, IL-1β/MDSC axis) or secreting carcinogens (e.g., aflatoxins). Concurrently, fungi and bacteria exhibit synergistic or antagonistic interactions within the microbiome, influencing the immune microenvironment and therapeutic response. Modulating the fungal microbiome (e.g., via antifungal agents, heat-killed fungi, or combined immunotherapy) may enhance antitumour immunity. Preliminary validation of this therapeutic potential has emerged from certain preclinical and clinical trials (e.g., itraconazole, ketoconazole).

Future prospects

Future fungal cancer research will progress from "correlation" towards "causation", utilizing single-cell sequencing and spatial omics to identify pro- or anti-cancer fungi, while integrating multi-kingdom interaction maps encompassing bacteria, viruses and archaea. Technologically, standardized protocols for ITS, 18S and metagenomic sequencing will be established, alongside developing fungal enrichment sequencing and multi-omics AI models, culminating in a tumor fungal ecosystem database. Clinically, fungal-bacterial combined biomarkers will be promoted for early screening, prognosis, and immunotherapy response prediction. Repurposed antifungal drugs like itraconazole and ketoconazole will be utilized, alongside developing low-toxicity nanoformulations and fungal metabolite adjuvants.

Research will explore fecal fungal transplantation, attenuated engineered fungi, and personalized 'fungal prescriptions'. Industrial advancement will drive synthetic biology-engineered medicinal fungi, targeted delivery systems, and mycobiome diagnostic kits. Societal efforts must overcome the bias of 'prioritizing bacteria over fungi' by establishing interdisciplinary fungal-cancer alliances. Government investment should concurrently develop ethical frameworks, antimicrobial resistance surveillance, and toxicity assessment protocols. Ultimately, this will realize mycobiome-driven precision diagnostics and therapeutics, benefiting cancer patients.