This article unpacks the key mechanisms behind this paradox, with a focus on the emerging roles of diet, the gut bacterium Lactobacillus johnsonii, and specific microbial metabolites.

Why Some Patients with Obesity Respond Better to ICIs

The obesity paradox in ICI treatment is mechanistically complex, but several interconnected pathways have been identified in recent research.

Chronic Low-Grade Inflammation and the Adipose–Immune Axis

Obesity creates a state of chronic, low-grade inflammation—sometimes called "meta-inflammation"—that can paradoxically prime the immune system. This altered immune environment, driven by the adipose–immune axis, can shift the tumor microenvironment in ways that make tumors more susceptible to checkpoint blockade .

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.

This article unpacks the key mechanisms behind this paradox, with a focus on the emerging roles of diet, the gut bacterium Lactobacillus johnsonii, and specific microbial metabolites.

Why Some Patients with Obesity Respond Better to ICIs

The obesity paradox in ICI treatment is mechanistically complex, but several interconnected pathways have been identified in recent research.

Chronic Low-Grade Inflammation and the Adipose–Immune Axis

Obesity creates a state of chronic, low-grade inflammation—sometimes called "meta-inflammation"—that can paradoxically prime the immune system. This altered immune environment, driven by the adipose–immune axis, can shift the tumor microenvironment in ways that make tumors more susceptible to checkpoint blockade .

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.