Fig. 4

Effects of the intratumoral microbiota on enhancing antitumor immunity. The intratumoral microbiota may enhance antitumor immunity and immunotherapy efficacy via mechanisms including STING signaling activation, T and NK cell activation, TLS production, and intratumoral microbiota-derived antigen presenting. (1) STING signaling activation: The intratumoral Bifidobacterium can activate DCs via the STING signaling pathway. A. muciniphila can produce STING agonists to induce IFN-I secretion by intratumoral monocytes, further promoting macrophage reprogramming and the crosstalk between NK and DC. (2) T and NK cell activation: The intratumoral Saccharopolyspora, Lachnoclostridium, EBV, and HBV, etc. can enhance antitumor immunity by promoting CD8⁺ T cell recruitment and activation mediated by intratumoral microbiota-derived CXCL9, CXCL10 and CCL5, which further prolongs patient survival. TMAO secreted by Clostridiales could trigger the PERK-mediated ER stress to induce tumor cell pyroptosis, which enhances antitumor immunity mediated by CD8⁺ T cells. A high-salt diet can increase Bifidobacterium and intratumoral localized, leading to enhanced NK cell function and tumor regression through the elevated by-product-hippurate. (3) TLS production: The intratumoral H. hepaticus induces Tfh cell- and B cell-dependent antitumor immune responses, which drives the maturation of tertiary lymphoid structures. (4) Intratumoral microbiota-derived antigen presenting: Furthermore, bacterial antigens can be seized by tumor cells or DCs, which further induces the responses of tumor-specific T cells