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Background As the most powerful professional antigen-presenting cell, dendritic cells (DCs), can effectively activate tumor-specific cytotoxic T lymphocyte responses through antigen cross-presentation (XPT), which involves endosome escape and subsequent degradation by ubiquitin-proteasome system of the exogenous tumor antigen in cytosol. Unfortunately, this important function is often compromised in the tumor microenvironment.Methods To recover the function of DCs in the antitumor settings, in the present study, we applied PROTAC (proteolysis-targeting chimera) principle in DC vaccine design by chemically linking a small molecular ligand of E3 ubiquitin ligase lenalidomide to a protein antigen ovalbumin (OVA), wrapped in membrane-penetrating nanoparticles calcium carbonate (CaCO 3), which combined both antigen endosome escape and proteasome degradation in DCs.Results The antitumor efficacy of the DC vaccines prepared by the chimeric antigen-containing nanoparticles, lenalidomide-OVA-CaCO 3 (LOC), termed as LOC-DCs, was found to be much higher than that of normal DC vaccines prepared by OVA wrapped in the same CaCO3 particles (OC-DCs), due mechanistically to the accelerated ubiquitination of OVA antigen and its subsequent degradation in the cytosol for major histocompatibility complex I-associated XPT. Interestingly, the antitumor efficacy of the LOC-DC vaccines we made was also proven to be better than that of LOC antigen vaccines in situ, because the LOC-DC vaccines were optimally activated by the chimeric LOC in vitro in terms of C-C motif chemokine receptor 7 (CCR7) and co-stimulatory molecule upregulation for their lymph node migration and T cell stimulation, respectively, in vivo.Conclusions Together, we established a proof of concept for PROTAC in the DC vaccine design by linking E3 ligase to a protein model antigen, which can be readily replaced with other identified pathogenic antigens to elicit robust cytotoxic immune responses against tumors or viral diseases, and thus has serious implications in the clinics.