Neoantigen-based immunotherapy is a promising treatment option for many types of cancer. However, its efficacy and abscopal effect are limited by impotent neoantigens, high treatment costs, and complications due to action of adjuvants. Here, the design and synthesis of nanovaccines are reported, based on self-adjuvanted, polymer nanoparticles with in vivo neoantigen-harvesting and molecular activating capabilities. These nanovaccines inhibit tumor growth significantly and prolong the survival of tumor-bearing mice in both colon carcinoma 26 (CT26) and B16-F10 tumor models. Mechanistic studies suggest that as-synthesized nanovaccines can promote dendritic cell maturation and accumulation expeditiously in lymph nodes, leading to the expansion of cytotoxic CD8+ T cells. Moreover, these nanovaccines elicit abscopal effects in CT26 and B16-F10 tumors without the need for adjuvants or immune checkpoint inhibitors. Combined with an anti-PD-L1 antibody, nanovaccines can evoke robust, long-term memory immune response, as evidenced by tumor growth inhibition and high survival rates (∼ 67%) over 90 days. These results highlight the potential of using self-adjuvanted nanovaccines as a simple, safe, and affordable strategy to boost neoantigen-based cancer immunotherapy. © 2020 Wiley-VCH GmbH.