In-situ trichosanthin-IL2/pectin dynamic hydrogel activates dendritic cells and reverses T cell exhaustion for post-operative cancer therapy

Postoperative recurrence and metastasis of triple-negative breast cancer (TNBC) remain major clinical challenges due to immunosuppression and poor immune recognition of residual cancer cells. Here, we present a novel polysaccharide-protein hydrogel implant, composed of a trichosanthin (TCS)-IL2 fusion protein crosslinked with oxidized pectin, designed for sustained local immunotherapy following tumor resection. TCS is a plant-derived protein with immune-stimulatory properties. This in-situ forming gel (termed TL-pectin gel) delivers the TCS-IL2 (TL) protein to enhance dendritic cell (DC) maturation, improve antigen presentation, and reverse T-cell exhaustion, thereby stimulating tumor-specific cytotoxicity. In a mouse breast cancer model, the TL-pectin hydrogel effectively inhibited local tumor recurrence and reduced lung and brain metastases, demonstrating its potential to improve postoperative outcomes. Mechanistic studies indicated that TCS activated the NF-κB pathway, enhanced cytokine secretion and CD8 + T-cell differentiation, and IL2 maintained T-cell proliferation and activity. The hydrogel showed excellent biocompatibility and functioned as a controlled-release system to form a localized immunostimulatory microenvironment. This study suggests that TL-pectin gel is a promising candidate for clinical translation, offering a potential approach for adjuvant cancer immunotherapy.