Fusobacterium nucleatum manipulates host autophagy to promote its intracellular survival and treatment resistance in nasopharyngeal carcinoma

TL;DR

This study shows how a specific type of bacteria helps cancer cells resist treatment by disrupting a key cellular process.

Contribution

The study reveals a novel mechanism by which Fusobacterium nucleatum promotes treatment resistance in nasopharyngeal carcinoma.

Findings

Fusobacterium nucleatum, particularly Fna C2, survives in cancer cells by inhibiting autophagy.

The FadA protein disrupts autophagy by targeting RAB7A for degradation via TRIM28.

High F. nucleatum colonization correlates with poor outcomes in NPC patients.

Abstract

Growing evidence highlights the existence and tumor-promoting role of intratumoral bacteria in various types of cancers. However, the mechanisms enabling the intracellular survival of these microorganisms remain poorly understood, impeding the development of microbiota-targeting anticancer strategies.

A transcriptomics analysis was used to identify the disease-related bacteria in nasopharyngeal carcinoma (NPC). Cell-bacteria coculture assay, cell viability assay, and mouse xenograft tumor model were used for functional investigation. Immunofluorescence, quantitative PCR analysis, RNA sequencing, immunoblot analysis, co-immunoprecipitation and mass spectrometry were utilized in mechanistic research. Fluorescent in situ hybridization in NPC specimens and clinical data were used for prognosis analysis.

We discovered that the Fusobacterium nucleatum (F. nucleatum), especially the C2 clade of F. nucleatum subsp. animalis (Fna C2), acts as an intracellular pathogen and exhibits distinct colonization advantages in NPC by inhibiting autophagy flux in host cells. Mechanistically, the virulence protein FadA of Fna C2 increases the ubiquitination and promotes the degradation of Ras-related protein RAB7A by enhancing the interaction between RAB7A and the E3 ligase TRIM28, which thus impairs the autophagosome-lysosome fusion and the autophagy machinery. The dysfunctional autophagy not only enables the persistent intracellular survival of F. nucleatum but also contributes to the treatment resistance of NPC. Clinically, a high intratumoral F. nucleatum colonization is associated with tumor relapse and poor outcome in NPC patients.

Our findings elucidate a key mechanism by which F. nucleatum survives and promotes treatment resistance in NPC, providing a microbiological prognosis indicator for NPC patients.

The online version contains supplementary material available at 10.1186/s12943-026-02581-1.

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