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SUMMARYImmunotherapies are used as adjuvant therapies for cancers. However, knowledge of how traditional cancer treatments affect immunotherapies is limited. Using mouse models, we demonstrate that tumor-draining lymph nodes (TdLNs) are critical for tumor antigen-specific T-cell response. However, removing TdLNs concurrently with established primary tumors did not affect the immune checkpoint blockade (ICB) response on localized secondary tumor due to immunotolerance in TdLNs and distribution of antigen-specific T cells in peripheral lymphatic organs. Notably, treatment response improved with sequential administration of 5-fluorouracil (5-FU) and ICB compared to concurrent administration of ICB with 5-FU. Immune profiling revealed that using 5-FU as induction treatment increased tumor visibility to immune cells, decreased immunosuppressive cells in the tumor microenvironment, and limited chemotherapy-induced T-cell depletion. We show that the effect of traditional cytotoxic treatment, not TdLNs, influences immunotherapy response in localized secondary tumors. We postulate essential considerations for successful immunotherapy strategies in clinical conditions.Graphic abstractThe effects of tumor-draining lymph nodes (TdLNs) resection and a combination of cytotoxic chemotherapy on immune checkpoint blockade therapies are evaluated in this study. TdLNs resection was adverse in eliciting an antitumor immune response in early-stage tumors, but not in late-stage tumors. Further, sequential treatments with cytotoxic chemotherapy and immunotherapy showed better tumor control compared to concurrent combinatorial treatments.