Synergizing CXCL9 with BRD4-PROTAC Using Nanochaperone Boosts Robust T Cell-Dependent Antitumor Immune Responses for Cancer Immunotherapy

The efficacy of cancer immunotherapy is greatly restricted by insufficient infiltration of cytotoxic T lymphocytes and immunosuppressive microenvironment in tumor tissue. Here a potent strategy to address the limitations by combination therapy of chemokine (CXCL9) with BRD4-PROTAC (dBET6) using the unique mixed-shell polymeric micelle (MSPM)-based nanochaperone (nChap) delivery platform is reported. CXCL9 significantly enhances the intratumoral infiltration of CD8+ T cells while dBET6 induces tumor cell immunogenic cell death (ICD) and downregulates the interferon-gamma (IFN gamma)-triggered programmed death ligand 1 (PD-L1) expression, synergizing to boost robust T cell-dependent antitumor immunity responses to enhance cancer immunotherapy is demonstrated. Moreover, this nano-CXCL9/dBET6 exhibits reduced systemic toxicity, prolonged half-life, and enhanced tumor accumulation in comparison to free drugs. This study provides a promising strategy for efficient cancer immunotherapy. A potent strategy is developed to address the major two hurdles of cancer immunotherapy (insufficient infiltration of cytotoxic T lymphocytes and immunosuppressive tumor microenvironment) by combination therapy of chemokine (CXCL9) with BRD4-PROTAC (dBET6) using unique nanochaperone delivery platform. CXCL9 significantly enhances the intratumoral infiltration of CD8+ T cells while dBET6 induces tumor cell ICD and downregulates the IFN gamma-triggered PD-L1 expression. image