Radiotherapy, although widely used for cancer therapy, always triggers changes in tumor microenvironment (TME) that lead to radioresistance and immunosuppression. In particular, during X-ray irradiation, hypoxia exacerbation would reduce radiosensitivity of tumor cells, while programmed cell death ligand 1 (PD-L1) upregulation impairs antitumor immune responses and exacerbates DNA damage repair, collectively resulting in severe T cell exhaustion and unsatisfactory therapeutic effect. Herein, we developed a liposomal nanodrug, C/J-Lipo, to simultaneously encapsulate a biological enzyme and a bromodomain containing 4 (BRD4) inhibitor for tumor-targeting delivery and TME modulation. Among C/J-Lipo, catalase could catalyze the decomposition of the excess HO in tumors and improve TME oxygenation. Meanwhile, JQ1 as a BRD4 inhibitor after being taken by cancer cells could downregulate PD-L1 expression in both cellular membrane and cytosol, inhibiting PD-1/PD-L1 interaction and DNA damage repair. By alleviating hypoxia and downregulating PD-L1 expression, C/J-Lipo reverses T cell exhaustion in TME. Altogether, C/J-Lipo-based radiotherapy significantly inhibited tumor growth and meanwhile triggered immunogenic cell death (ICD) of cancer cells to activate T cell-mediated anti-tumor immunity. After the combination with αPD-1, C/J-Lipo-based radio-immunotherapy achieved complete tumor eradication and metastases elimination in 80 % mice with survival over 80 days. This multifunctional nanodrug represents a promising strategy to overcome therapy resistance and optimize radio-immunotherapy outcomes.