Gum Disease Protein Mfa1 Supercharges Anti–PD-L1 Cancer Immunotherapy in Mice

A protein best known for helping the oral bacterium Porphyromonas gingivalis stick to surfaces in the mouth may have an unexpected second life in oncology. In a study published in Cancer Immunology, Immunotherapy, researchers report that Mfa1, an adhesion protein from the gum-disease-associated bacterium, acts as a powerful immune stimulant in mice and significantly improves the anti-tumor effect of anti–PD-L1 antibody therapy. The finding, led by Eun-Koung An, Wei Zhang, Minjun Jung and senior authors Wonpil Im and Jun-O Jin, spans institutions in China, South Korea and the United States, and points to a bacterial protein as a candidate adjuvant for cancer immunotherapy.

The work builds on a well-established precedent in bacterial immunology. FimH, an adhesion molecule from Escherichia coli, is known to activate immune cells including dendritic cells and T cells. Mfa1 plays an analogous adhesive role for P. gingivalis, the keystone pathogen of chronic periodontitis, but its immunostimulatory potential had not been thoroughly explored. To close that gap, the team synthesized and extracted recombinant Mfa1 from E. coli, giving them a purified protein they could test in controlled experiments without exposing animals or cells to the live pathogen.

The first line of evidence came from dendritic cells, the sentinels of the adaptive immune system. When bone marrow-derived dendritic cells from mice were exposed to recombinant Mfa1, the cells upregulated co-stimulatory molecules and major histocompatibility complex (MHC) molecules in a dose-dependent manner. These surface proteins are the molecular handshake through which dendritic cells license T cells: co-stimulatory molecules provide the activating signal, while MHC molecules present tumor or microbial antigens for T cell recognition. Their coordinated increase is a hallmark of dendritic cell maturation and a prerequisite for mounting a strong T cell response.

Those in vitro observations translated into living animals. When C57BL/6 mice received Mfa1, the proportion and absolute number of dendritic cells in the spleen increased, and the cells showed enhanced expression of C-C chemokine receptor type 7, or CCR7. CCR7 is the trafficking receptor that guides mature dendritic cells from peripheral tissues to lymph nodes, where they present antigen to naive T cells, so its upregulation is a functional indicator of dendritic cell migration and maturation rather than a mere surface marker change. Mfa1 treatment also elevated the numbers of the two principal conventional dendritic cell subsets, cDC1 and cDC2, further upregulated co-stimulatory and MHC molecules, and raised levels of pro-inflammatory cytokines in vivo, painting a picture of systemically awakened antigen-presenting machinery.

To identify the receptor through which Mfa1 exerts these effects, the researchers turned to computational structural biology. Using AI-based protein complex prediction together with all-atom molecular dynamics simulations, they modeled the interaction of Mfa1 with Toll-like receptors, the innate immune sensors that recognize microbial molecular patterns. The simulations showed that Mfa1 binds TLR2 with high structural confidence and stability, while its binding to TLR4 was markedly less stable. This kind of integrated modeling approach allows researchers to rank candidate receptor interactions before committing to lengthy experimental validation, and here it produced a clear, testable prediction.

The prediction held up under genetic scrutiny. The immune-activating effects of Mfa1 that were readily observed in wild-type mice were absent in TLR2-knockout mice, confirming that the protein’s activity depends on TLR2 signaling. This loss-of-function experiment is the mechanistic anchor of the study: it demonstrates that Mfa1 is not a nonspecific irritant but a ligand that engages a defined innate immune receptor, triggering the downstream maturation program in dendritic cells that the team had characterized in detail.

With innate immunity activated, the question became whether the response extended to the adaptive arm. Repeated Mfa1 treatment enhanced the intracellular production of two signature inflammatory cytokines, interferon-gamma and tumor necrosis factor-alpha, in both CD4-positive helper T cells and CD8-positive cytotoxic T cells. Interferon-gamma is a central coordinator of anti-tumor immunity, activating macrophages and increasing antigen presentation, while tumor necrosis factor-alpha contributes directly to inflammatory tumor cell killing. Robust cytokine production by both T cell compartments indicates that Mfa1-driven dendritic cell maturation successfully translates into T cell activation, the effector arm that checkpoint blockade therapies are designed to unleash.

The culmination of the study came in a Lewis lung carcinoma model, a widely used preclinical system for lung cancer immunotherapy. When the researchers combined Mfa1 with an anti–PD-L1 antibody, the checkpoint inhibitor’s anti-tumor efficacy was enhanced. Anti–PD-L1 antibodies work by blocking the interaction between PD-L1 on tumor or immune cells and PD-1 on T cells, releasing a molecular brake on T cell activity. But many tumors respond poorly to this class of drug, often because the immune system has not been sufficiently primed to recognize and attack the tumor in the first place. An adjuvant like Mfa1, which expands and matures dendritic cell populations and drives T cell activation, addresses that priming deficit and can convert a cold, unresponsive tumor microenvironment into one more receptive to checkpoint blockade.

The implications reach beyond lung cancer. Immune adjuvants are a critical but underdeveloped component of cancer immunotherapy, and most current options are synthetic or highly engineered molecules. A bacterial adhesion protein that engages TLR2, a receptor with a well-characterized role in immune activation, offers a biologically grounded scaffold for adjuvant design. The authors suggest that Mfa1 may serve as a potential immunostimulatory adjuvant to enhance cancer immunotherapy, and the combination of computational receptor prediction, genetic validation and efficacy testing in a tumor model provides a coherent proof-of-concept chain from molecule to mechanism to therapeutic outcome.

Considerable work remains before any clinical translation. The findings are confined to mouse models, and the dose, schedule, safety profile and immunogenicity of a recombinant bacterial protein in humans would require extensive evaluation. There is also an inherent irony to navigate: P. gingivalis is a destructive periodontal pathogen, and any therapeutic use of its components must ensure that adhesive or inflammatory properties relevant to infection are not transferred to patients. Nevertheless, the study adds Mfa1 to a growing list of microbial molecules being repurposed for immunotherapy, and it demonstrates how AI-guided structural prediction can accelerate the identification of immune receptor ligands. For a field searching for ways to make checkpoint inhibitors work in more patients, a protein from an unlikely oral microbe has emerged as a candidate worth watching.

Subject of Research: Immunostimulatory effects of the Porphyromonas gingivalis adhesion protein Mfa1 as an adjuvant for anti–PD-L1 cancer immunotherapy

Article Title: Porphyromonas gingivalis adhesion protein Mfa1 enhances the anti-cancer effect of anti–PD-L1 antibody by immune activation

Article References: An, E.-K., Zhang, W., Jung, M., Park, H.-B., Kim, S.-J., Ryu, D., Jeong, E., Lee, M., Xu, Y., Lee, P. C. W., Im, W., & Jin, J.-O. (2026). Porphyromonas gingivalis adhesion protein Mfa1 enhances the anti-cancer effect of anti–PD-L1 antibody by immune activation. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04587-6

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04587-6

Keywords: Mfa1, Porphyromonas gingivalis, TLR2, dendritic cells, anti–PD-L1, immune adjuvant, cancer immunotherapy, T cell activation, lung carcinoma, molecular dynamics simulation, CCR7, interferon-gamma