Gut microbiota influence the antitumour efficacy of immune checkpoint blockade1-6, but the mechanisms of action have not been fully elucidated. Here, we show that a new strain of the bacterial genus Hominenteromicrobium (designated YB328) isolated from the faeces of patients who responded to programmed cell death 1 (PD-1) blockade augmented antitumour responses in mice. YB328 activated tumour-specific CD8+ T cells through the stimulation of CD103+CD11b- conventional dendritic cells (cDCs), which, following exposure in the gut, migrated to the tumour microenvironment. Mice showed improved antitumour efficacy of PD-1 blockade when treated with faecal transplants from non-responder patients supplemented with YB238. This result suggests that YB328 could function in a dominant manner. YB328-activated CD103+CD11b- cDCs showed prolonged engagement with tumour-specific CD8+ T cells and promoted PD-1 expression in these cells. Moreover, YB238-augmented antitumour efficacy of PD-1 blockade treatment was observed in multiple mouse models of cancer. Patients with elevated YB328 abundance had increased infiltration of CD103+CD11b- cDCs in tumours and had a favourable response to PD-1 blockade therapy in various cancer types. We propose that gut microbiota enhance antitumour immunity by accelerating the maturation and migration of CD103+CD11b- cDCs to increase the number of CD8+ T cells that respond to diverse tumour antigens.
© 2025. The Author(s).

Natural killer (NK) cells can control metastasis through cytotoxicity and IFN-γ production independently of T cells in experimental metastasis mouse models. The inverse correlation between NK activity and metastasis incidence supports a critical role for NK cells in human metastatic surveillance. However, autologous NK cell therapy has shown limited benefit in treating patients with metastatic solid tumors. Using a spontaneous metastasis mouse model of MHC-I+ breast cancer, we found that transfer of IL-15/IL-12-conditioned syngeneic NK cells after primary tumor resection promoted long-term survival of mice with low metastatic burden and induced a tumor-specific protective T cell response that is essential for the therapeutic effect. Furthermore, NK cell transfer augments activation of conventional dendritic cells (cDCs), Foxp3-CD4+ T cells and stem cell-like CD8+ T cells in metastatic lungs, to which IFN-γ of the transferred NK cells contributes significantly. These results imply direct interactions between transferred NK cells and endogenous cDCs to enhance T cell activation. We conducted an investigator-initiated clinical trial of autologous NK cell therapy in six patients with advanced cancer and observed that the NK cell therapy was safe and showed signs of effectiveness. These findings indicate that autologous NK cell therapy is effective in treating established low burden metastases of MHC-I+ tumor cells by activating the cDC-T cell axis at metastatic sites.
© 2024, Huang, Lai, Liao et al.