EISA in Tandem with ICD to Form In Situ Nanofiber Vaccine for Enhanced Tumor Radioimmunotherapy

Abstract Radiotherapy (RT) can produce a vaccine effect and remodel a tumor microenvironment (TME) by inducing immunogenic cell death (ICD) and inflammation in tumors. However, RT alone is insufficient to elicit a systemic antitumor immune response owing to limited antigen presentation, immunosuppressive microenvironment, and chronic inflammation within the tumor. Here, a novel strategy is reported for the generation of in situ peptide‐based nanovaccines via enzyme‐induced self‐assembly (EISA) in tandem with ICD. As ICD progresses, the peptide Fbp‐G D F D F D pY (Fbp‐pY), dephosphorylated by alkaline phosphatase (ALP) forms a fibrous nanostructure around the tumor cells, resulting in the capture and encapsulation of the autologous antigens produced by radiation. Utilizing the adjuvant and controlled‐release advantages of self‐assembling peptides, this nanofiber vaccine effectively increases antigen accumulation in the lymph nodes and cross‐presentation by antigen‐presenting cells (APCs). In addition, the inhibition of cyclooxygenase 2 (COX–2) expression by the nanofibers promotes the repolarization of M2‐macrophages into M1 and reduces the number of regulatory T cells (Tregs) and myeloid‐derived suppressor cells (MDSCs) required for TME remodeling. As a result, the combination of nanovaccines and RT significantly enhances the therapeutic effect on 4T1 tumors compared with RT alone, suggesting a promising treatment strategy for tumor radioimmunotherapy.