A Nanomodulator Enhances Radiotherapy‐Induced In Situ Cancer Vaccine by Promoting Antigen‐Presenting of Tumor‐Associated Macrophage

Radiotherapy (RT) can induce an in situ vaccine effect by promoting the generation of tumor neoantigens, yet this effect is insufficient to elicit robust antitumor immune responses. Although the abundant tumor-associated macrophages (TAMs) in tumor tissue, as members of antigen-presenting cells, have been shown to capture antigens efficiently, the proteomic analysis, that TAMs is demonstrated exhibit up-regulated cysteine protease in lysosomes that leads to tumor antigen degradation. Inhibiting cysteine protease activity can promote the antigen-presenting of TAMs. Based on this, a nanomodulator (Ft-E64/Hf@Lipo) is developed, combining radiosensitizer hafnium (Hf) and the cysteine protease inhibitor E64, which cooperatively reinvigorated the antigen presentation of TAMs. Ft-E64/Hf@Lipo sensitized RT generated abundant tumor neoantigens, and then E64/antigens, along with the apoptotic tumor cells, trafficked to TAMs via efferocytosis. The reprogrammed TAMs with attenuated lysosomal function effectively presented tumor antigens and activated CD8⁺ T cells. In vivo studies demonstrated that the nanomodulator significantly enhanced systemic antitumor immune responses following RT, realizing excellent therapeutic efficacy against large, treatment-resistant CT26 tumors in combination with anti-PD-1 therapy. The work provides a promising approach for enhancing the in situ vaccine effect of RT to improve its clinical benefits.