Chemotherapy (CT) is an efficient cancer treatment modality as it can directly inhibit tumor growth and various CT agents can induce immunogenic cell death (ICD) against malignancies. However, CT with high dosage could corrupt the immune system severely, leading to inadequate anti-tumor immunogenicity against distant or recurrence tumors. Currently, combined CT with immunotherapy is considered an advanced therapeutic modality by exploiting immunological boosting agents. However, it is still an insurmountable challenge for immunological boosting agents to counteract CT-induced immunosuppression. Hence, we hypothesized that cancer immunotherapy continuously with mild CT will improve tumor inhibition efficiency. Therefore, we proposed a novel “prime-boost” strategy to enhance the anti-tumoral immune responses by alleviating CT-mediated immunosuppression through cancer vaccine priming plus chemo-ICD boosting (“vaccine + ICD”). In vivo experiments have shown long-term immune response and improved treatment efficiency for primary and distant tumor inhibition in “vaccine + ICD” group compared to the conventional “ICD + vaccine” group. The inhibition rate (IR) for distant tumor in “vaccine + ICD” group (94.6%) is considerably higher than “ICD + vaccine” group (65.8%). More remarkably, immunological memory was established for long-term anti-tumor immune surveillance. Our study for the first time provides a novel “prime-boost” strategy for amplifying anti-tumor immune responses.