Self-transforming hydrogel mimicking tertiary lymph nodes to activate cGAS-STING pathway for enhanced antitumor immunotherapy.

Abstract

The nonspecific distribution of tertiary lymph node (TLS)-inducing drugs may trigger autoimmune diseases. We developed a self-transforming chitosan hydrogel to act as a biomimetic TLS. The chitosan hydrogel solution was peritumorally injected in bacteria-colonized tumors in mice followed by the rapid in situ gelation. After killing tumor cells and intratumoral bacteria by doxorubicin and cefotaxime, the hydrogel efficiently adsorbed bacterial pathogen-associated molecular patterns, tumor cell-derived damage-associated molecular patterns, and tumor-associated antigens. These danger signals greatly potentiated immune cell recruitment into the hydrogel and sufficiently activated dendritic cells (DCs) by the absorbed DNA-mediated cGAS-STING activation. The activated DCs converted T cells into cytotoxic T cells, and these activated immune cells migrated through the pores of hydrogels into the tumor tissues, effectively remodeling the immunosuppressive microenvironment, thereby inhibiting the tumor growth and metastasis. These findings demonstrate a previously unidentified method to establish a safe, easy-to-control, and effective biomimetic TLS that offers a promising strategy for updating current combined immunotherapy against various tumors.