Sustained-release hydrogel system for preventing postoperative tumor recurrence through synergistic immune signal enhancement for T cell activation.

Surgical resection remains the first-line clinical treatment for most solid tumors; however, postoperative recurrence and metastasis constitute the predominant causes of cancer-related mortality. To address this challenge, we developed an in situ injectable, sustained-release hydrogel drug delivery system that achieved prolonged, synergistic therapeutic effects through combination immunotherapy following tumor resection. This system, designated as TL-Lip-CD80Fc@Gel, consists of a chitosan/β-glycerophosphate (β-GP) thermosensitive hydrogel matrix loaded with tumor lysate (TL), mannose-decorated R848 liposomes (R848-Man-Lips), and a fusion protein of CD80 and fragment crystallizable region (CD80Fc). After administered at the resection site, the hydrogel precursor underwent a sol-gel phase transition and formed a drug depot when exposed to physiological temperature, facilitating the sustained release of its therapeutic components. The TL enhanced both the immunogenicity and the levels of tumor antigens, while the R848-Man-Lips effectively targeted dendritic cells (DCs) to promote their maturation. Both factors synergistically enhanced antigen presentation by DCs, strengthening signal 1 for T cell activation. Simultaneously, the CD80Fc can directly reinforce signal 2, the costimulatory signal required for robust T cell activation. These components synergistically amplified the in vivo immune response while prolonging its duration, thereby presenting a potent immunotherapy strategy to prevent postoperative tumor recurrence. Overall, the TL-Lip-CD80Fc@Gel system holds substantial potential for clinical application in the treatment of post-surgical cancer, offering an effective and durable approach to mitigate recurrence risks.