Background: Hypofractionated radiotherapy (HFRT) of the primary tumor can induce abscopal effects in metastatic cancer, which could be enhanced by adding PD-1 immunotherapy (IO) and low-dose radiotherapy (LDRT) of distant disease. However, this strategy remains with suboptimal efficacy. Translational research has shown that LDRT primarily modulates the immune microenvironment of tumors in the irradiated area, a mechanism shared by anti-angiogenic therapy (AAT). Therefore, this study aimed to compare the efficacy (abscopal responses and cytokine levels in the tumor microenvironment) between HFRT+IO+AAT and HFRT+IO+LDRT. Methods: Bilateral mouse tumor models were divided into seven groups for various treatments (Table 1). After treatment, blood and tumor samples of mice were collected for analysis. We evaluated clinical effects of HFRT+IO+AAT in 4 patients with unirradiated lung metastases in a currently-accruing phase Ib study of stereotactic body radiotherapy (SBRT) plus anlotinib (AAT) with or without toripalimab (PD-1 IO) in driver mutation-negative non-small cell lung cancer (NCT05021328). Results: The results of animal studies are shown in Table 1. HFRT to the primary tumor combined with AAT and IO enhanced the abscopal response in secondary tumor compared to HFRT, HFRT+IO, HFRT+AAT, IO+AAT, as well as HFRT+LDRT+IO. The most noteworthy secondary tumor control was observed in mice receiving HFRT+IO+AAT. The enhanced abscopal responses were associated with increased infiltration of CD8+ effector T cells, increased expression of IFN-γ and levels of TNF-α. From the prospective trial population, 4 unirradiated lung lesions in the HFRT+IO+AAT cohort decreased by an average of 48% in size (n=3 partial response, n=1 stable disease). No grade 3 treatment-related toxicity was observed. Conclusions: HFRT+IO+AAT is a promising therapeutic combination that may optimize abscopal responses, potentially even further than HFRT+LDRT+IO. This new “triple therapy” was safe and efficacious in patients and deserves further study.