Self-transforming hydrogel mimicking tertiary lymph nodes to activate cGAS-STING pathway for enhanced antitumor immunotherapy
Fei Wang, Yukun Zeng, Manqi Yan, Ziqi Zhou, Lingzi Feng, Fei Yang, Wei Zhao, Yong Hu
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.