Insights into the Relationship Between the Gut Microbiome and Immune Checkpoint Inhibitors in Solid Tumors

Abstract

Immunotherapy with immune checkpoint inhibitors represents a revolutionary approach to the treatment of solid tumors, including malignant melanoma, lung cancer, and gastrointestinal malignancies. Anti-CTLA-4 and anti-PD-1/PDL-1 therapies provide prolonged survival for cancer patients, but their efficacy and safety are highly variable. This review focuses on the crucial role of the gut microbiome in modulating the efficacy and toxicity of immune checkpoint blockade. Studies suggest that the composition of the gut microbiome may influence the response to immunotherapy, with specific bacterial strains able to promote an anti-tumor immune response. On the other hand, dysbiosis may increase the risk of adverse effects, such as immune-mediated colitis. Interventions aimed at modulating the microbiome, including the use of probiotics, prebiotics, fecal microbial transplantation, or dietary modifications, represent promising strategies to increase treatment efficacy and reduce toxicity. The combination of immunotherapy with the microbiome-based strategy opens up new possibilities for personalized treatment. In addition, factors such as physical activity and nutritional supplementation may indirectly influence the gut ecosystem and consequently improve treatment outcomes in refractory patients, leading to enhanced patient responses and prolonged survival.

Keywords: cancer treatment; fecal microbiota transplantation; immune checkpoint inhibitors; probiotics; solid tumors; the gut microbiome.

Figure 1

The associations between the gut microbiome composition, immune checkpoint inhibitors, and immune responses against cancer. A favorable gut microbiome and high bacterial diversity enhance the maturation of DCs and T cell priming, leading to the release of specific cytokines that drive the expansion of effector CD8+ T cells. Activation of tumor-specific CD8+ T cells and higher levels of serum IFN-γ, TNF-α, and granzyme B contribute to cancer cell death. Modulating the immune cell responses by commensal bacteria enhances tumor sensitivity to ICIs. In contrast, an unfavorable microbiome composition and decreased bacterial diversity are associated with elevated levels of Treg cells and MDSCs, leading to reduced amounts of cytotoxic CD8+ T cells and cancer immune evasion. Additionally, intestinal dysbiosis can create a tumor microenvironment less conducive to effective CD8+ T cell activity. Abbreviations: CTLA-4, cytotoxic T lymphocyte-associated protein 4; DC, dendritic cell; ICIs, immune checkpoint inhibitors; IFN-γ, interferon-gamma; IL-10, interleukin-10; MDSCs, myeloid-derived suppressor cells; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; SCFAs, short-chain fatty acids; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; Treg cell, regulatory T cell.