AIM: To explore the efficacy and safety of fecal microbiota transplantation combined with immune checkpoint inhibitors (ICIs) for malignant tumor patients with failed multi line anti-tumor treatment and concomitant cachexia, and to explore the changes in blood immunity and intestinal microbial environment in patients. METHODS: Five patients with malignant tumors who failed multi line anti-tumor treatment were enrolled and treated with ICIs combined with fecal microbiota transplantation. The efficacy was evaluated every 2-3 cycles, and adverse reactions were observed. Fecal 16srRNA gene sequencing and serum immunological indicators were dynamically detected. RESULTS: Except for one patient who died 2.5 months after transplantation due to excessive tumor burden at enrollment, the overall survival of the remaining four patients were extended (7.4, 8.3, 28.5, 52.3 months). One patient with multiple intracranial metastases of lung adenocarcinoma significantly reduced the intracranial metastasis after intestinal microbiota transplantation and almost disappeared. The serum IL-2, IL-10, TGF-β and other indicators of patients increased rapidly and then slowly decreased with the increase of transplantation time, and finally were higher than before transplantation, with statistical differences. 16srRNA gene sequencing analysis revealed significant differences in the overall distribution of gut microbiota in patients after transplantation, gradually approaching healthy transplant donors. All patients did not experience grade 2 or above adverse reactions, and the safety was good. CONCLUSION: For patients with malignant tumors, the combination of fecal microbiota transplantation and immunotherapy may improve their quality of life, serum immune environment, and intestinal microbiota composition, have a positive impact on survival prognosis, and are safe and controllable, opening up new treatment methods for end-stage patients.