A Near-Infrared-II Antibody-Photosensitizer Conjugate for Photoimmunotherapy of Advanced Pancreatic Cancer

Abstract Pancreatic cancer (PC) is a highly lethal malignancy, characterized by frequent late-stage diagnosis and limited response to available treatments. Photoimmunotherapy, which combines the localized tumor ablation of phototherapy with the systemic immune activation of immunotherapy, presents a promising strategy. However, its success is often hampered by insufficient accumulation of therapeutic agents at the tumor site. To address this challenge, we developed a novel antibody-photosensitizer conjugate, named αPD-L1@AIE, by conjugating a multifunctional phototheranostic agent with αPD-L1 antibody for targeted photoimmunotherapy of PC. The incorporation of αPD-L1 not only facilitates tumor-specific targeting but also acts as an immune checkpoint inhibitor. Upon 660 nm laser irradiation, this phototheranostic agent enables NIR-II fluorescence imaging and simultaneously induces potent immunogenic cell death (ICD) via combined photodynamic and photothermal therapy. Following localized phototherapy, the released tumor-associated antigens from ICD initiate a robust antitumor immune response. Such a response is synergistically amplified by αPD-L1, which together alleviates immunosuppression via Treg cell depletion and M2-like macrophage repolarization, thereby promoting a marked increase in cytotoxic T lymphocyte infiltration and granzyme B production. Consequently, the aforementioned photoimmunotherapy approach effectively suppresses tumor growth and inhibits spontaneous metastasis, demonstrating a powerful and transformative paradigm for advanced PC management.