Antibodies targeting CTLA-4 have been successfully used in cancer immunotherapy. This study shows that the antitumor effects of CTLA-4 blockade depend on specific Bacteroides species, particularly B. fragilis and B. thetaiotaomicron. In mice and patients, T cell responses specific for these bacteria were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA-4 blockade, but this defect was overcome by gavage with B. fragilis, immunization with B. fragilis polysaccharides, or adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with CTLA-4 antibodies favored the outgrowth of B. fragilis with anticancer properties. The study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade. Ipilimumab, a monoclonal antibody targeting CTLA-4, is used to treat metastatic melanoma but often causes immune-related adverse events, particularly in the gut. The gut microbiota is crucial for the immunomodulatory effects of CTLA-4 blockade. The study compared the therapeutic efficacy of CTLA-4-specific antibodies in SPF and germ-free mice, finding that the gut microbiota was required for the anticancer effects of CTLA-4 blockade. The study also showed that CTLA-4 blockade can induce intestinal lesions, which are dependent on the gut microbiota. The microbiota-dependent immunostimulatory effects of CTLA-4 blockade depend on the mobilization of lamina propria CD11b+ DCs that can process zwitterionic polysaccharides and mount IL-12-dependent TH1 immune responses against B. fragilis capsular polysaccharides. However, these effects do not appear to result from TLR2/TLR4-mediated innate signaling in the context of compromised gut tolerance. The study analyzed the composition of the gut microbiome before and after treatment with ipilimumab in 25 melanoma patients, finding that the microbiome composition affected the efficacy of CTLA-4 blockade. Fecal microbial transplantation from patients with different microbiome compositions showed that those with a specific microbiome composition (cluster C) had better responses to CTLA-4 blockade. The study also showed that the abundance of immunogenic Bacteroides species in the gut affects the efficacy of CTLA-4 blockade. Finally, the study showed that the efficacy of CTLA-4 blockade is influenced by the microbiota composition, particularly B. fragilis and B. thetaiotaomicron. The microbiota composition affects IL-12-dependent TH1 immune responses, which facilitate tumor control in mice and patients while sparing intestinal integrity. The study also shows that theAntibodies targeting CTLA-4 have been successfully used in cancer immunotherapy. This study shows that the antitumor effects of CTLA-4 blockade depend on specific Bacteroides species, particularly B. fragilis and B. thetaiotaomicron. In mice and patients, T cell responses specific for these bacteria were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA-4 blockade, but this defect was overcome by gavage with B. fragilis, immunization with B. fragilis polysaccharides, or adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with CTLA-4 antibodies favored the outgrowth of B. fragilis with anticancer properties. The study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade. Ipilimumab, a monoclonal antibody targeting CTLA-4, is used to treat metastatic melanoma but often causes immune-related adverse events, particularly in the gut. The gut microbiota is crucial for the immunomodulatory effects of CTLA-4 blockade. The study compared the therapeutic efficacy of CTLA-4-specific antibodies in SPF and germ-free mice, finding that the gut microbiota was required for the anticancer effects of CTLA-4 blockade. The study also showed that CTLA-4 blockade can induce intestinal lesions, which are dependent on the gut microbiota. The microbiota-dependent immunostimulatory effects of CTLA-4 blockade depend on the mobilization of lamina propria CD11b+ DCs that can process zwitterionic polysaccharides and mount IL-12-dependent TH1 immune responses against B. fragilis capsular polysaccharides. However, these effects do not appear to result from TLR2/TLR4-mediated innate signaling in the context of compromised gut tolerance. The study analyzed the composition of the gut microbiome before and after treatment with ipilimumab in 25 melanoma patients, finding that the microbiome composition affected the efficacy of CTLA-4 blockade. Fecal microbial transplantation from patients with different microbiome compositions showed that those with a specific microbiome composition (cluster C) had better responses to CTLA-4 blockade. The study also showed that the abundance of immunogenic Bacteroides species in the gut affects the efficacy of CTLA-4 blockade. Finally, the study showed that the efficacy of CTLA-4 blockade is influenced by the microbiota composition, particularly B. fragilis and B. thetaiotaomicron. The microbiota composition affects IL-12-dependent TH1 immune responses, which facilitate tumor control in mice and patients while sparing intestinal integrity. The study also shows that the