<p>Personalized vaccines demonstrate remarkable potential in leveraging tumor-specific adaptive immunity for cancer therapy. Nevertheless, current platforms face persistent challenges, including premature systemic clearance and imprecise antigen-presenting cell targeting, culminating in transient and inefficient antitumor immunity. Furthermore, the technical complexity, extended timelines, and prohibitive costs required for tumor-specific neoantigen identification continue to impede the clinical translation of personalized cancer vaccines. Here, we report a tumor-derived extracellular vesicle-based scaffold vaccine that elicits robust and durable antitumor immunity for personalized cancer immunotherapy. Following subcutaneous administration, the in situ-formed hydrogel vaccine serves as a sustained reservoir for tumor-derived extracellular vesicle antigens and adjuvants while recruiting antigen-presenting dendritic cells to accumulate within the scaffold. Upon exposure to this antigen-rich depot, immature dendritic cells undergo efficient activation, with subsequently matured dendritic cells migrating to draining lymph nodes, where they induce potent and persistent tumor-specific CD8⁺ T-cell responses that suppress tumor progression across multiple murine models. Specifically, when using tumor-derived extracellular vesicles isolated from surgically excised tumor tissues, the patient-tailored vaccines demonstrate remarkable efficacy in preventing postoperative recurrence. Our findings validate the robust and durable therapeutic efficacy of this vaccine platform, highlighting its potential as a customizable strategy for personalized cancer immunotherapy.</p>