The Obesity Paradox in Cancer Immunotherapy: How Diet, Lactobacillus johnsonii, and Microbial Metabolites Boost Treatment Response

Histone Lactacylation of CD8+ T Cells

A 2025 study revealed a specific epigenetic mechanism linking obesity to better ICI responses. Obesity-driven glycolysis increases lactate production, which is transported into CD8+ T cells via the MCT1 transporter. This drives lysine lactylation of histones, upregulating PD-1 expression on T cells—making them more sensitive to PD-1 blockade .

Gut Microbiome Alterations

Obesity significantly reshapes the gut microbiota, and these microbial changes influence ICI outcomes. Several bacterial species enriched in obesity are associated with enhanced checkpoint blockade efficacy . One of the most-studied organisms in this context is Lactobacillus johnsonii.

Macrophage PD-1 Induction

A 2024 Nature study found that obesity induces PD-1 expression on macrophages. While this can suppress anti-tumor immunity, it may also create an environment that is more responsive to PD-1/PD-L1 blockade, contributing to the obesity paradox .

The Role of High-Fat Diet and Lactobacillus johnsonii

Diet is a major driver of gut microbiome composition. Among the bacterial species that thrive under high-fat diet (HFD) conditions, Lactobacillus johnsonii stands out.

HFD Selects for L. johnsonii

Among several Lactobacillus strains, L. johnsonii showed the strongest resistance to HFD-induced carcinogenesis in murine models. Only live bacteria had anti-tumor efficacy, indicating that active bacterial metabolism is required .

In HFD-exposed mice, L. johnsonii converts conjugated bile acids into chenodeoxycholic acid (CDCA), which decelerates HFD-induced colorectal cancer progression by inducing mitochondrial dysfunction and oxidative stress in tumor cells .

L. johnsonii Enhances ICI Efficacy via Metabolites

L. johnsonii abundance in the gut is positively correlated with responsiveness to immune checkpoint blockade in multiple cancer types . Oral gavage of L. johnsonii in mice increased CD8+ T cell infiltration into tumors and sensitized tumors to αPD-1 therapy .

Key metabolites involved include:

• Indole-3-propionic acid (IPA): L. johnsonii collaborates with Clostridium sporogenes to produce IPA from tryptophan. IPA modulates the stemness program of CD8+ T cells, promoting the generation of progenitor exhausted CD8+ T cells (Tpex) with enhanced anti-tumor activity .
• Nicotinic acid (NA): In hepatocellular carcinoma, higher intratumoral L. johnsonii levels correlated with increased IFN-γ+PD-1+CD8+ T cells, with nicotinic acid identified as a key metabolite .

The Microbial Metabolite Desaminotyrosine (DAT): A Separate Pathway

Desaminotyrosine (DAT) is a distinct microbial metabolite that enhances ICI efficacy—but it is not produced by L. johnsonii.

DAT Boosts Immunotherapy via Type I Interferon Signaling

Oral DAT supplementation in mice delayed tumor growth and enhanced anti-CTLA-4 and anti-PD-1 therapy. The mechanism involves activation of type I interferon signaling, leading to increased activated T cells and natural killer (NK) cells in the tumor microenvironment .

DAT Is Produced by Other Gut Bacteria

DAT is produced by bacteria such as Clostridium orbiscindens, not by L. johnsonii. The current evidence does not show L. johnsonii as a DAT producer .

What Is Not Yet Established

No published study has demonstrated a single, coherent pathway connecting high-fat diet → L. johnsonii expansion → DAT production → enhanced ICI. The DAT mechanism and the L. johnsonii mechanism come from separate research groups and involve different microbial species. The specific three-way synergy sometimes hypothesized is not yet confirmed in the peer-reviewed literature—it may represent a conflation of two distinct microbiome-ICI pathways.

L. johnsonii's ICI-enhancing effects appear to involve IPA (via CD8+ T cell stemness modulation) or nicotinic acid, not desaminotyrosine .

A clinical trial (NCT07191405) is currently testing chemotherapy and immunotherapy combined with L. johnsonii in patients with advanced solid tumors, which may provide further clarity .

Bottom Line

The evidence strongly supports that:

• High-fat diets enrich L. johnsonii in the gut.
• L. johnsonii independently enhances ICI responses, likely via IPA or nicotinic acid pathway.
• Separately, the microbial metabolite DAT enhances ICI responses via type I interferon signaling.

Understanding these parallel pathways offers new opportunities for microbiome-based cancer therapies, but researchers caution that the full picture—including whether these pathways converge—remains an active area of investigation.