Microbes offer engineering strategies to combat cancer

immune cells exist with interactive networks that dictate good health and disease, including cancer, both within and beyond the gut1–3. This emerging paradigm linking gut bac teria with extraintestinal cancer builds upon earlier work that tumour microenvironments interact with systemic immune and metabolic networks4, and, more specifically, with microbial– immune networks2,5,6. In this way, gut microbes influence cancer outcomes. The concept that a unified microbe–host holo biont (defined as the whole host organism plus resident microbiota) influences progression of cancer, and even cardiovascular disease and mental health, is both clinically relevant and capti‐ vating6. Given that microbes generally out‐ number host cells 10:1, it follows logically that crosstalk between the gut microbiota and host immunity is continuous and reciprocal throughout the host’s life1,7. In fact, microbe– immune interactions constitute part of a vast gut–immune–brain signalling axis7 that con‐ tinuously modulates IFNγ, CD4+ regu latory T (TREG) cells and host inflammatory tone3,6. It remains to be determined how vast an effect microbial strategies will have on what are now intractable disease challenges. A new study by Vetizou et al.8 sheds light on this issue, reveal‐ ing that the gut microbiota modulates patient responses to cancer immunotherapy. Specifically, Vetizou et al.8 discovered that the antitumour effects of the cytotoxic T‐lymphocyte protein 4 (CTLA‐4) block‐ ade immunotherapy agent ipilimumab, against the cancer target. Immunomodulatory effects of Bacteroides spp. were evidenced by induction of a type 1 T helper (TH1) response in lymph nodes draining the tumour site. In this setting, immune checkpoint blockade of CTLA‐4 led to host TH1‐cell inflammatory responses that favoured certain symbiotic microbe populations contributing to thera‐ peutic efficacy with fewer adverse effects. These results have profound implications not only for cancer immunotherapy, but also for novel strategies using microbiome engineer‐ ing in cancer prevention and treatments separate from immunotherapy (FIG. 1). The gut microbial dynamics documented by Vetizou et al.8 during immunotherapy also provide insight into complex microbe– immune feedback loops during host homeo‐ stasis. Although it is well established that microbial infections stimulate host TH1 responses and IFNγ in order to extinguish a mucosal pathogen and stimulate tissue repair, excessive and/or chronic inflamma‐ tion are detrimental to the host. Thus, an immune balance between pro‐inflammatory and anti‐inflammatory activities is the ulti‐ mate goal. The potential to creatively harness the microbe‐driven immune balance hints at an approved negative regulator of T‐cell acti‐ vation, rely in part upon resident gut bac teria. Using samples from patients undergoing immunotherapy for small cell lung carcinoma or malignant melanoma, combined with elegant germ‐free and adoptive T‐cell transfers in animal models, they showed that certain Bacteroides spp. are critical for host immuno‐ stimulatory responses and therapeutic success G U T M I C R O B I OTA