Immune checkpoint blockade (ICB) can elicit anti-cancer response against tumors growing at normal organs while sparing adjacent tissues. However, many orthotopic tumors respond poorly to ICB therapy due to the lack of pre-existing immune effector cells. Here, we describe a vaccine strategy that induces protective immunity and benefits ICB therapy. An injectable hydrogel platform that forms scaffold subcutaneously was applied to deliver autologous cancer cells undergoing oncolysis (ACCO) as immunogenic antigen source and toll-like receptor 9 agonists (CpG) as additional adjuvant. When administered as a prophylactic, the hydrogel-based vaccine, denoted as (ACCO+CpG)@Gel, successfully built a durable and tumor antigen-specific immune memory against subsequent challenges with orthotopic engraftment of autologous tumors including melanoma, colon carcinoma, and lung carcinoma. Although the vaccination did not completely prevent tumor occurrence, tumors orthotopically established in vaccinated mice acquired significant enhancement in tumor-infiltrating CD8+ T cells and intratumoral PD-L1 expression, which ameliorated the immune status and rendered the originally irresponsive tumors responsible to anti-PD-L1 therapy. Further treatment with PD-L1 blockade therapy efficiently delayed the tumor growth and prolonged the survival of these orthotopic cancer models. Thus, without the need for precisely delivering immunoactivatory agents to tumor or locally remodeling tumor microenvironment, "priming" intractable or inaccessible tumors for subsequent ICB therapy could be achieved by prophylactic vaccination with (ACCO+CpG)@Gel. These findings highlighted (ACCO+CpG)@Gel as a generalized framework of protective vaccine strategy that could be broadly applicable to potentiate ICB therapy against multiple types of orthotopic tumors growing in different regions.