Bidirectional Modulation of the Tumor Immune Microenvironment by Gut Microbiota-Derived Indoles: Mechanisms and Therapeutic Potential.

The tumor immune microenvironment (TIME) plays a decisive role in cancer progression and therapeutic response. Emerging evidence highlights gut microbiota-derived indole metabolites, produced from dietary tryptophan, as key regulators of tumor immunity. These metabolites function through complex metabolic networks and exert dual immunomodulatory effects: they can enhance antitumor immunity by promoting CD8+ T cell stemness, increasing tumor immunogenicity, and relieving immunosuppression, while also suppressing immunity by inducing regulatory T cells (Tregs), M2 macrophage polarization, and anti-inflammatory cytokine production. This review systematically summarizes the biosynthetic pathways and microbial sources of major indole compounds, and discusses their context-dependent roles in shaping the TIME via aryl hydrocarbon receptor (AhR)-dependent and -independent mechanisms. Unlike previous reviews that often extrapolate findings from non-tumor inflammation models to cancer without adequate contextualization, we critically evaluate evidence from both tumor and non-tumor models, with explicit distinction between direct tumor-relevant findings and speculative insights for the tumor immune microenvironment (TIME). Special attention is given to the therapeutic potential of indoles as adjuvants to immune checkpoint blockade and their promise in precision immuno-oncology. By integrating microbiology, immunology, and metabolomics, we aim to provide a theoretical foundation for developing indole-based strategies to overcome immunotherapy resistance and improve clinical outcomes.