The study investigates the role of gut microbiota in the efficacy of CTLA-4 blockade immunotherapy. Key findings include: 1. **Microbiota Dependency**: CTLA-4 blockade in mice and patients is associated with specific T cell responses to *Bacteroides* species, particularly *B. thetaiotaomicron* and *B. fragilis*. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA-4 blockade. 2. **Mechanisms of Action**: Oral gavage with *B. fragilis*, immunization with *B. fragilis* polysaccharides, or adoptive transfer of *B. fragilis*-specific T cells restored the antitumor effects in antibiotic-treated or germ-free mice. 3. **Fecal Microbial Transplantation**: Fecal microbial transplantation from melanoma patients treated with CTLA-4 antibodies favored the growth of *B. fragilis*, which has anticancer properties. 4. **Clinical Relevance**: Analysis of gut microbiome in melanoma patients showed that cluster C individuals, characterized by a higher abundance of *Bacteroides* spp., had better responses to CTLA-4 blockade compared to cluster B individuals. 5. **Toxicity and Efficacy**: Intestinal reconstitution with *B. fragilis* and *Burkholderiales* reduced colitis induced by CTLA-4 blockade without compromising antitumor effects. 6. **Th1 Immune Responses**: CTLA-4 blockade induced TH1 immune responses against *B. fragilis* and *B. thetaiotaomicron*, which facilitated tumor control while preserving intestinal integrity. 7. **Future Directions**: The study suggests that modulating the gut microbiota, particularly with *Bacteroides* spp., could enhance the efficacy of CTLA-4 blockade immunotherapy in cancer patients.The study investigates the role of gut microbiota in the efficacy of CTLA-4 blockade immunotherapy. Key findings include: 1. **Microbiota Dependency**: CTLA-4 blockade in mice and patients is associated with specific T cell responses to *Bacteroides* species, particularly *B. thetaiotaomicron* and *B. fragilis*. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA-4 blockade. 2. **Mechanisms of Action**: Oral gavage with *B. fragilis*, immunization with *B. fragilis* polysaccharides, or adoptive transfer of *B. fragilis*-specific T cells restored the antitumor effects in antibiotic-treated or germ-free mice. 3. **Fecal Microbial Transplantation**: Fecal microbial transplantation from melanoma patients treated with CTLA-4 antibodies favored the growth of *B. fragilis*, which has anticancer properties. 4. **Clinical Relevance**: Analysis of gut microbiome in melanoma patients showed that cluster C individuals, characterized by a higher abundance of *Bacteroides* spp., had better responses to CTLA-4 blockade compared to cluster B individuals. 5. **Toxicity and Efficacy**: Intestinal reconstitution with *B. fragilis* and *Burkholderiales* reduced colitis induced by CTLA-4 blockade without compromising antitumor effects. 6. **Th1 Immune Responses**: CTLA-4 blockade induced TH1 immune responses against *B. fragilis* and *B. thetaiotaomicron*, which facilitated tumor control while preserving intestinal integrity. 7. **Future Directions**: The study suggests that modulating the gut microbiota, particularly with *Bacteroides* spp., could enhance the efficacy of CTLA-4 blockade immunotherapy in cancer patients.