A multifunctional hydrogel for obesity-associated tumor immunotherapy and postsurgical wound healing promotion

The multidimensional complexity between metabolism and inflammation within the obese tumor microenvironment (OTME) poses substantial barriers to postsurgical immunotherapy and wound management. Herein, we engineered a multifunctional hydrogel (Lipo/CXB@Hydrogel) through covalent conjugation of dopamine-crosslinked oxidized hyaluronic acid and a ROS-sensitive linker, co-delivering the non-steroidal anti-inflammatory drug celecoxib (CXB) and the lipid metabolism modulator Lipofermata (Lipo) to facilitate T cell immunotherapy and wound healing. The unique multi-dynamic-bond crosslinked structure endows the hydrogel with excellent self-healing, tissue adhesiveness and mechanical properties. The implanted Lipo/CXB@Hydrogel degrades and releases CXB to suppress hyperinflammation and enhance intratumoral cytotoxic T lymphocyte (CTL) infiltration, while Lipo inhibits the predatory uptake of fatty acids by tumor cells in the OTME for competing metabolic resources of intratumoral infiltrated CTLs. Importantly, such a cascaded immunological effect of Lipo/CXB@Hydrogel treatment amplifies CTL proliferation and activity specifically through targeting the arachidonic acid (AA)/COX-2/PGE2 signaling axis, a central hub linking lipid metabolism and inflammation, initiating a long-lasting immune response to suppress colorectal tumor postsurgical recurrence and metastasis in obesity contexts. Moreover, the hydrogel can easily repeatedly close the reopened wounds and promote skin regeneration. Thus, this multifunctional hydrogel may provide a promising strategy for postsurgical obese tumor immunotherapy and wound closure.