Radiotherapy has shown remarkable clinical success using high doses of radiation to kill cancer cells and shrink tumors; however, tumor resistance to radiation is still an intractable challenge to enhance radiation damage to tumor tissue. Here, we show a capacity of tumor-penetrating peptide LyP-1 that enhanced the effect of radiation on 4T1 tumor. We injected LyP-1 peptide into the tumor model through the tail vein and irradiated mice subsequently. The radiation treatment combined with LyP-1 exhibited significant regression of the tumor compared to radiation alone or LyP-1 alone. We analyzed the tumor immune microenvironment after treatment, the expression of myeloid-derived suppressor cells (MDSCs) both in the spleen and the tumor were effectively suppressed. Besides, LyP-1 could drive macrophage polarization to the M1 phenotype and regulate its immune function. We also evaluated the safety of this strategy, the results demonstrated that radiation combined with LyP-1 exhibited excellent in vivo safety and tumor suppression. Therefore, LyP-1 can be a promising radiosensitizer candidate to enhance radiation efficacy as well as induce reactivation of the immune system.

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