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

Abstract 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‐γ (IFNγ)‐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.