Supramolecular STING-Hydrogel Spatiotemporally Boosts Tumor-Derived Extracellular Vesicle-Based Personalized Vaccine for Enhanced Cancer Immunotherapy.

Abstract

Personalized vaccines represent a promising approach for cancer treatment by eliciting tumor-specific immune responses. However, their development faces persistent challenges, including the laborious and costly process of neoantigen identification, which substantially delays vaccine production. Moreover, conventional platforms suffer from rapid systemic clearance and inefficient delivery to antigen-presenting cells (APCs), leading to only transient and weak immune activation. Here, we report a STING-agonist-integrated hydrogel system designed for localized delivery of tumor-derived extracellular vesicles (TEVs) to achieve robust and durable antitumor immunity. Upon subcutaneous administration, the in situ formed hydrogel vaccine acts as a depot for antigen-rich TEVs and STING agonists. We demonstrate that this vaccine promotes dendritic cells (DCs) recruitment and establishes an immune-permissive niche through spatiotemporal control over antigen-adjuvant distribution and prolonged APC-antigen engagement. Within this niche, DCs efficiently internalize and process TEVs under STING-mediated activation. These matured DCs subsequently migrate to draining lymph nodes, where they initiate potent and sustained tumor-specific T-cell responses. Our results show that rapidly producible personalized vaccines derived from melanoma TEVs effectively inhibit tumor growth. In a postoperative breast cancer model, patient-tailored TEV vaccines also markedly prevent tumor recurrence and metastasis. This readily customizable platform represents a robust and translatable strategy for personalized cancer immunotherapy.