Multifunctional hydrogel integrating phototherapy and tumor microenvironment remodeling combined with immunotherapy for synergistic treatment of HCC

This study develops a multifunctional hydrogel that achieves highly effective treatment of hepatocellular carcinoma (HCC) by combining phototherapy with immunotherapy and remodeling tumor microenvironment (TME). The hydrogel is prepared via dynamic Schiff base crosslinking between carboxymethyl chitosan and four-arm PEG benzaldehyde, incorporating polyvinylpyrrolidone-modified Bi 2 WO 6-x (BWO-PVP) nanoparticles and fucoidan (Fu). In vitro studies demonstrate that the hydrogel exhibites good self-healing properties, injectability, and TME-responsive degradation behavior. Under 808 nm laser irradiation, it generates substantial hyperthermia and reactive oxygen species, leading to significant inhibition of HepG2 cell proliferation. Moreover, the hydrogel can release Fu to suppresse the activation of cancer-associated fibroblasts (CAFs), which contributing to TME remodeling. In H22 hepatoma-bearing mice, the hydrogel can also load the STING agonist (cyclic dinucleotide, CDN), thereby suppressing tumor growth and reversing immunosuppressive TME conditions. Hence, this combinatory strategy provides a promising platform for enhancing HCC treatment through integrated phototherapy, TME regulation and immunotherapy.