The non-bacterial oncobiome: the role of the mycobiome and virome in tumor plasticity

Abstract Tumor plasticity, the capacity of malignant cells to undergo reversible phenotypic switching, is a fundamental driver of lineage diversion and therapeutic resistance. While the bacterial microbiome is a recognized modulator of the tumor microenvironment (TME), the non-bacterial oncobiome, comprising the mycobiome (fungi) and virome (viruses), represents a critical but under-explored frontier in cellular adaptability. This review synthesizes current evidence regarding the mechanistic contributions of fungal and viral constituents to tumor plasticity and characterizes the molecular cross-talk that facilitates host cell reprogramming. We conducted a structured narrative synthesis of literature indexed in PubMed, Scopus, and Web of Science (2020–2026), focusing on high-throughput studies such as ITS sequencing, metagenomics NGS (mNGS), and single-cell network analyses. We specifically evaluated evidence concerning the activation of host pattern recognition receptors and the subsequent transcriptional rewiring of lineage-defining markers. Emerging data indicate that fungal dysbiosis, particularly involving Candida and Malassezia species, triggers the Dectin-1/STAT3 signaling axis, a known inducer of epithelial-mesenchymal transition (EMT). Concurrently, the virome, ranging from integrated oncoviruses to reactivated endogenous retroviruses (ERVs), is shown to hijack the Wnt/ β-catenin pathway, enforcing a progenitor-like stemness state. This inter-kingdom synergy promotes an immune-excluded niche, effectively shielding plastic sub-populations from cytotoxic stress and targeted therapies. The non-bacterial oncobiome provides genomic momentum and inflammatory cues necessary to lower the threshold for phenotypic switching. This review highlights that stabilizing the TME ecosystem through ecologically targeted therapy may be a prerequisite for overcoming drug resistance and improving clinical outcomes in refractory cancers.