A CXCR4-targeted immunomodulatory nanomedicine for photodynamic amplified immune checkpoint blockade therapy against breast cancer

Abstract

The therapeutic efficacy of immune checkpoint blockade (ICB) is critically compromised by inadequate T lymphocyte infiltration, low T cell-induced pro-inflammatory responses, and the accumulation of immunosuppressive cells within the tumor microenvironment (TME). In this work, a chimeric peptide-engineered immunomodulatory nanomedicine (designated as CXNP-CeBM) is developed for photodynamic amplified ICB therapy against breast cancer. CXNP-CeBM is composed of a CXCR4-targeting peptide ((C₁₆)₂-KLGASWHRPDK) loaded with the photosensitizer of Ce6 and the PD-1/PD-L1 inhibitor of BMS8. CXNP-CeBM specifically recognizes CXCR4 on breast cancer, thus suppressing CXCR4-mediated signaling pathways and enhancing the intracellular delivery of therapeutic agents. The photodynamic therapy (PDT) of CXNP-CeBM damages primary tumor cells to initiate immunogenic cell death (ICD), leading to the release of high mobility group box 1 (HMGB1) and the exposure of calreticulin (CRT). Simultaneously, the interruption of CXCR4 signaling reduces tumor fibrosis, promotes T-cell infiltration, and decreases the number of immunosuppressive cells, thereby enhancing the immunotherapeutic effect of ICB. Treatment with CXNP-CeBM would activate systemic anti-tumor immunity, leading to effective inhibition of both primary and lung metastatic tumors, while maintaining low systemic toxicity. This work provides a reliable strategy for the delivery of multi-synergistic agents, effectively activating breast cancer immunity through a multifaceted mechanism.

Statement of significance

Although immune checkpoint blockade (ICB) has shown great potential for malignant tumor therapy, its efficacy is compromised by immunosuppressive microenvironments. Herein, a CXCR4-targeted immunomodulatory nanomedicine (CXNP-CeBM) was constructed for photodynamic amplified ICB therapy of breast cancer. CXNP-CeBM could selectively deliver photosensitizers and PD-1/PD-L1 inhibitors to breast cancer cells that overexpressed the chemokine receptor CXCR4, while interrupting CXCR4 signaling to reduce tumor fibrosis, promote T-cell infiltration, and decrease the number of immunosuppressive cells. Moreover, CXNP-CeBM induced photodynamic therapy to trigger immunogenic cell death while downregulating the PD-L1 level to destroy immune evasion mechanisms, thus activating immunological cascades to treat both primary and lung metastatic tumors. This study provided a multi-synergistic strategy for breast cancer immunotherapy through a multifaceted mechanism.