Chemotherapy enhances cancer vaccine efficacy and expands stem-like TCF1+CD8+ T cells.

Therapeutic cancer vaccines are increasingly tested in clinical settings alongside standard-of-care treatments that often include chemotherapy, yet whether chemotherapy synergizes with cancer vaccines remains unclear. Here, we tested heterologous prime-boost viral vector vaccines in combination with various chemotherapy regimens. Both carboplatin plus paclitaxel (CarboTaxol) and cyclophosphamide improve vaccine efficacy and enhance antigen-specific CD8+ T cell responses. These chemotherapies act as immunological adjuvants independently of tumor presence. Mechanistically, CarboTaxol induces an early, antigen-independent expansion of stem-like T cell factor 1 (TCF1)+CD8+ T cells, an effect also observed in patients with different cancer types. Genetic or pharmacological disruption of TCF1 impairs the immunological adjuvant effect of CarboTaxol. Adding programmed cell death 1 (PD-1) blockade to viral vector vaccines and CarboTaxol further improves tumor control and survival. Together, these findings identify a TCF1-dependent mechanism underlying the immune adjuvant effect of chemotherapy and provide a rationale for clinical evaluation of this triple combination therapy.