Abstract
Radiotherapy (XRT) is often utilized to improve the immune checkpoint blockade response in cancer management. Such combination treatment can enhance the abscopal effect, facilitating a prolonged and durable systemic response. However, despite intense research efforts, only a minority of patients respond to this approach, and novel strategies to increase the abscopal effect are urgently needed. Here, the development of an intratumoral (i.t.) injectable nanofiber (NF)-based tumor immune niche (TIN) that converts XRT-treated tumors into an in situ cancer vaccine, eliciting robust systemic antitumor immunity, is reported. This NF-based immune niche incorporates redox-degradable anti-CTLA-4 (α-CTLA-4) nanogels (NGs) and interleukin-2 (IL-2) NGs for controlled release in hypoxic irradiated tumors, reversing the immunosuppressive tumor microenvironment into a pro-inflammatory microenvironment, and expanding the tumor-infiltrating CD8+ T cell population. Additionally, it is functionalized with polyinosinic-polycytidylic acid (poly(I:C)) to promote antigen-presenting cell maturation and prime neoantigen-specific CD8+ T cells. In vitro studies demonstrate TIN's ability to prime antigen-specific CD8+ T cells and increase antigen-specific cell-killing efficiency under in vitro immunosuppressive conditions. In vivo studies confirm TIN's ability to elicit robust systemic anticancer activity in mouse melanoma and colorectal cancer models without inducing severe immune-related adverse events.