A Peritumoral Injectable Hydrogel-Mediated PD-1 Blockade Plus Chemotherapy for Pancreatic Cancer Treatment

The dense stromal barrier of pancreatic cancer (PC) severely limits chemotherapeutic efficacy. Although combination therapy is a standard clinical approach, it often exacerbates systemic toxicity. To address the dual challenges of localized drug delivery and immune activation, we developed an injectable, multifunctional hydrogel system for the synergistic codelivery of an anti-PD-1 antibody and chemotherapeutic agents (gemcitabine/albumin-bound paclitaxel). This system is based on a novel, fully natural-source composite material─methacrylated silk fibroin (SilMA) and methacrylated chitosan (CSMA). Its core innovations include: in situ gelation via a mild LAP-photoinitiation process preserves antibody bioactivity and bioactive degradation products derived from the natural polymers, which may help establish a favorable peritumoral microenvironment. In an orthotopic PC mouse model, a single peritumoral injection of this hydrogel (HLGP group) significantly enhanced tumor infiltration of CD8+ T cells, suppressed tumor growth, and outperformed all control groups, including the free-drug combination group. This study presents a unique, integrated local delivery strategy capable of simultaneously overcoming the stromal barrier, reducing systemic exposure and enhancing immunotherapy efficacy, thereby offering a promising translational pathway for the treatment of pancreatic cancer.