The enhanced cancer nanovaccine by bidirectionally blocking CXCL12/CXCR4 axis to inhibit the recurrence and metastasis of triple-negative breast cancer

Abstract In situ cancer vaccine is a new method for cancer immunotherapy, however, the local immunosuppressive microenvironment of cancer tissue limits its immune response and therapeutic efficacy. The CXCL12/CXCR4 axis plays a key role in forming an immunosuppressive microenvironment. In this study, siCXCR4 (S) was used as an "immune adjuvant" and co-loaded with hydroxycamptothecin (HCPT) to develop an in situ cancer nanovaccine (HCPT/S@CaP/HA) for synergistically inhibiting the growth, recurrence and metastasis of triple negative breast cancer (TNBC). HCPT/S@CaP/HA actively targeted to orthotopic TNBC cells and cancer-associated fibroblasts (CAFs), induced the immunogenic death of orthotopic TNBC cells to promote the maturation of dendritic cells (DCs). Meanwhile, HCPT/S@CaP/HA also reduced the secretion of CXCL12 by CAFs and silenced the expression of CXCR4 in TNBC tissue to bidirectionally block the CXCL12/CXCR4 axis, thereby synergistically reversing immunosuppressive microenvironment, enhancing the infiltration and activity of cytotoxic T lymphocytes in orthotopic TNBC tissues, and subsequently inhibiting the growth of orthotopic TNBC. Moreover, HCPT/S@CaP/HA inhibited the recurrence of TNBC by synergistically increasing the percentage of memory T lymphocytes in the spleen tissue of mice, and it diminished the spontaneous lung metastasis of orthotopic TNBC by promoting the presentation of TNBC antigens and activating TNBC-specific immune responses immune responses. HCPT/S@CaP/HA is a potential in situ cancer nanovaccine for the immunotherapy of TNBC.