Programmable‐Responsive Cell‐Resident Polymeric Micelles for Granzyme B‐Steered Integrated Anti‐PD‐L1 Immunotherapy via Membrane Repair Interference

ABSTRACT

Despite the clinical promise of immune checkpoint blockade (ICB), its therapeutic performance in prostate cancer remains suboptimal due to membrane repair‐associated resistance and insufficient immune engagement. Herein, a programmable‐responsive cell‐resident micelle (PBAM) is engineered to integrate BAPTA (a calcium chelator), anti‐PD‐L1 antibody, and prochlorperazine (PCZ)/β‐cyclodextrin inclusion complexes within a pH/granzyme B (GzmB)‐dual‐responsive system, enabling spatiotemporally coordinated multidrug release for integrated anti‐PD‐L1 immunotherapy. PBAM selectively accumulates in tumors and undergoes acid‐triggered PCZ release, suppressing PI3K/Akt signaling and reducing endocytic uptake to maintain tumor cell surface anchoring. Upon ICB‐mediated immune activation, cytotoxic T lymphocytes (CTLs) secrete granzyme and perforin to induce tumor cell apoptosis while triggering GzmB‐responsive micellar degradation for BAPTA release, thereby disrupting Ca ²⁺ ‐dependent membrane repair and sensitizing tumor cells to CTL‐mediated cytotoxicity. This spatiotemporally coordinated cascade reinforces PD‐1/PD‐L1 blockade to overcome immune resistance, thereby restoring antitumor immunity and enhancing memory‐associated T‐cell responses, ultimately constraining tumor progression and recurrence.