An Ultrasound‐Responsive and In Situ Gelling Hydrogel Nanocomposite for Boosting Anti PD‐L1 Immunotherapy via Remodeling Aberrant ECM of Post‐Surgical Residual Cancer

Abstract Tumor recurrence and metastasis following surgery remain formidable challenges. Although that is a crucial factor in determining efficacy of postoperative immune treatment, the impact of surgery on tumor microenvironment (TME) is still understudied and the specific treatment options for residual cancer are unsatisfactory. Here, it is verified that abnormal extracellular matrix (ECM) of postsurgical residual cancer results in deteriorative hypoxia, immunosuppression, and hypo‐perfusion, which further promotes invasion and may hinder efficacy of immune checkpoint blockades (ICB). To adaptively potentiate ICB therapy in this context, an ultrasound‐responsive, visualized, and in situ gelling hydrogel nanocomposite (TPP ALG) is prepared through combining phase change nanoparticles and alginate solution for normalizing ECM with controllable delivery of tranilast. After injection and gelling with ions in situ, TPP ALG enables ultrasound visualized and responsive local delivery and long‐term retention, capable of normalizing ECM, improving hypoxia, remodeling immunosuppressive microenvironment, and enhancing ICB permeation for boosting immunotherapy. Ultimately, this TPP ALG and ICB synergistic treatment approach effectively inhibit local recurrence and lung metastasis post operation, thereby delaying survival. Therefore, based on clinical drug and biocompatible materials, the simple‐synthesized hydrogel nanocomposite holds great application prospects for boosting ICB and inhibiting postsurgical cancer recurrence and metastasis.