A ROS-Responsive Photothermal Hydrogel for Tumor Microenvironment Reprogramming and STING-Mediated Immune Engagement

Abstract

Photothermal therapy can induce local tumor cell death and trigger antitumor immune responses. However, its efficacy is often limited by insufficient lymph node immune priming and by sustained ROS generated from thermal stress, which suppress immune cell function. An oxidative-stress-responsive injectable hydrogel–nanoparticle composite (TP@PPM) was constructed by embedding MSA-2-loaded PEGylated polydopamine nanoparticles (PPM) into a TSPBA–PVA hydrogel. Upon near-infrared (NIR) irradiation, PPM mediated photothermal cytotoxicity, induced tumor-cell thermal stress and mitochondrial dysfunction, and generated reactive oxygen species (ROS), triggering immunogenic cell death. The relatively stable and diffusible H2O2 generated within the tumor microenvironment can enter the tumor interstitium and oxidize boronate ester crosslinks in the hydrogel, thereby promoting hydrogel degradation and enabling controlled PPM release. Then, the PPM accumulated in tumor-draining lymph nodes within 6 h and delivered MSA-2 to dendritic cells and activated the STING pathway. In vitro, TP@PPM attenuated MDSC-associated ROS accumulation and restored T cell proliferation to 44.8% in an MDSC-T cell coculture system. In vivo, TP@PPM combined with NIR irradiation promoted the infiltration of CD8+/CD4+ T cell and reduced pulmonary metastasis of the tumor. This hydrogel–nanoparticle composite platform helps overcome photothermal therapy-induced immune suppression, reduce oxidative stress in the TME, and inhibit tumor metastasis, offering a promising strategy for enhancing cancer immunotherapy.