Background: Liposomes deliver the drug to tumors based on enhanced permeability and retention (EPR) effects. Radiotherapy further prompts the distribution of liposomal drugs to tumor sites receiving radiotherapy by altering the tumor microenvironment. In addition, radiotherapy might enhance systemic antitumoral responses to immunotherapy. Herein, we aimed to explore safety and efficacy of radiotherapy in combination with irinotecan liposome, immunotherapy, and antiangiogenic therapy in advanced solid tumors patients (pts) that failed standard treatments. Methods: Anopen single-arm, multi-center, phase II study was conducted to enroll solid tumors pts who have failed standard treatments. Eligible pts would receive radiotherapy combined with irinotecan liposome followed by camrelizumab and apatinib. Radiotherapy of 24 Gy/3 fractions/3-10 days was given to the targeted lesions. Irinotecan liposome (80mg/m² i.v.) was administered once within 48 hours after radiotherapy and followed by camrelizumab (200mg i.v. q3w) and apatinib (250mg po qd) until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) of the irradiated lesions evaluated by the investigators as per RECIST V1.1. The secondary endpoints were disease control rate (DCR) and treatment-related adverse event (TRAE). Results: As of Dec 2021, 55 pts were enrolled includin 9 with biliary tract cancer, 8 with pancreatic cancer, 8 with sarcoma, 5 with lung cancer, 2 with liver cancer, 2 with cervical cancer, 2 with gastric cancer, and 22 with other cancer types. 26 (47.3%) pts failed at least 3 lines of therapy before enrollment. The median follow-up was 41 weeks and 42 pts can be evaluated. 15 partial response, 26 stable disease, and 1 progressive disease were achieved. The ORR and DCR of irradiated target lesions were 35.7% and 97.6%, respectively. The ORR and DCR of every cancer type are listed in table. TRAEs (all grades) occurred in 87.3% (48/55) pts. The most common grade 3-4 related TRAEs were lymphocyte count decreased (29.1%), white blood cell count decreased (10.9%), and anaemia (10.9%). Conclusions: The combination of radiotherapy, irinotecan liposome, camrelizumab, and apatinib demonstrated promising anti-tumor activity and well tolerance in various advanced solid tumors that failed standard treatments. Clinical trial information: NCT04569916.