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<p>Immune checkpoint blockade (ICB) has improved the cancer treatment, its application remains constrained by heterogeneous response rates and immune-related adverse events. While gut microbiome modulation represents a promising avenue to optimize ICB, rationally selected probiotics with defined mechanistic actions are critically lacking. Here, we selected <i>Lactobacillus fermentum</i> GR-3 (<i>L. fermentum</i> GR-3), a food-derived strain pre-screened for exceptional gastrointestinal resilience (maintaining &gt; 10<sup>7</sup>&#xa0;CFU/mL), antioxidant activity (87.4% DPPH-Scavenging efficiency), and immunomodulatory potential, as an oral combination strategy to enhance anti-PD-1 therapy. In the MC38 murine colorectal cancer model, oral <i>L. fermentum</i> GR-3 synergistically enhanced ICB efficacy, yielding significantly greater tumor suppression than anti-PD-1 monotherapy (51.7% volume reduction vs. untreated controls), while attenuating therapy-associated weight loss. Locally within the tumor microenvironment (TME), the combination therapy promoted dendritic cell maturation (MHC-II⁺ DCs reaching 56.0%), favored pro-inflammatory macrophage polarization (M1 increased to 20.8%, while M2 reduced to 2.57%), and suppressed regulatory T cell infiltration (Tregs decreased to 2.32%). These shifts strongly correlated with enhanced cytotoxic responses, with&#xa0;Granzyme B⁺ CD8⁺ T cells reaching 40.4% (doubling the effect of PD-1 monotherapy). Mechanistically, <i>L. fermentum</i> GR-3 colonization partially reversed tumor-associated gut dysbiosis, enriching short-chain fatty acid (SCFA)-producing consortia (e.g., <i>Lachnospiraceae</i> and <i>Bacteroides</i>) and increasing intestinal SCFA concentrations <b>(</b>e.g., propionic and butyric acids recovering to 70.13 and 26.07&#xa0;μM/g, respectively)). This microbial-metabolic shift was accompanied by upregulated expression of mucosal tight junction genes (<i>ZO-1</i>, <i>Occludin</i>). Furthermore, <i>L. fermentum</i> GR-3 facilitated a balanced immune response. Systemically, it alleviated oxidative stress and buffered peripheral inflammatory signals, contributing to immune homeostasis in non-tumor tissues (spleen and colon). Collectively, these findings position <i>L. fermentum</i> GR-3 as a grounded, translatable strategy to simultaneously enhance ICB efficacy and improve therapeutic tolerability.</p>

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Food-Derived Limosilactobacillus fermentum GR-3 Enhances Anti–PD-1 Immunotherapy Efficacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月16日

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  • Wei Xiang,
  • Qi Yang,
  • Jing Ji,
  • Hui Qiao,
  • Aman Khan,
  • El-Sayed Salama,
  • Chunlan Mao,
  • Ying Wu,
  • Xiangkai Li

摘要

Immune checkpoint blockade (ICB) has improved the cancer treatment, its application remains constrained by heterogeneous response rates and immune-related adverse events. While gut microbiome modulation represents a promising avenue to optimize ICB, rationally selected probiotics with defined mechanistic actions are critically lacking. Here, we selected Lactobacillus fermentum GR-3 (L. fermentum GR-3), a food-derived strain pre-screened for exceptional gastrointestinal resilience (maintaining > 107 CFU/mL), antioxidant activity (87.4% DPPH-Scavenging efficiency), and immunomodulatory potential, as an oral combination strategy to enhance anti-PD-1 therapy. In the MC38 murine colorectal cancer model, oral L. fermentum GR-3 synergistically enhanced ICB efficacy, yielding significantly greater tumor suppression than anti-PD-1 monotherapy (51.7% volume reduction vs. untreated controls), while attenuating therapy-associated weight loss. Locally within the tumor microenvironment (TME), the combination therapy promoted dendritic cell maturation (MHC-II⁺ DCs reaching 56.0%), favored pro-inflammatory macrophage polarization (M1 increased to 20.8%, while M2 reduced to 2.57%), and suppressed regulatory T cell infiltration (Tregs decreased to 2.32%). These shifts strongly correlated with enhanced cytotoxic responses, with Granzyme B⁺ CD8⁺ T cells reaching 40.4% (doubling the effect of PD-1 monotherapy). Mechanistically, L. fermentum GR-3 colonization partially reversed tumor-associated gut dysbiosis, enriching short-chain fatty acid (SCFA)-producing consortia (e.g., Lachnospiraceae and Bacteroides) and increasing intestinal SCFA concentrations (e.g., propionic and butyric acids recovering to 70.13 and 26.07 μM/g, respectively)). This microbial-metabolic shift was accompanied by upregulated expression of mucosal tight junction genes (ZO-1, Occludin). Furthermore, L. fermentum GR-3 facilitated a balanced immune response. Systemically, it alleviated oxidative stress and buffered peripheral inflammatory signals, contributing to immune homeostasis in non-tumor tissues (spleen and colon). Collectively, these findings position L. fermentum GR-3 as a grounded, translatable strategy to simultaneously enhance ICB efficacy and improve therapeutic tolerability.