Boosting Checkpoint Blockade Immunotherapy with T Cell Membrane Redox Homeostasis Regulation and Deep Learning Enhanced NIR-II Imaging.

Abstract

Immune checkpoint blockade therapy has revolutionized clinical oncotherapy by intercepting immunosuppressive pathways in tumor tissues. Nevertheless, the therapeutic efficacy is limited by a multidimensional immunosuppressive tumor microenvironment, which impedes the activity of tumor-infiltrating immune cells and undermines treatment outcomes. In this study, a zwitterionic polymer is designed for the conjugation and traceless release of a checkpoint inhibition antibody (Atezolizumab), while concurrently enabling the restoration of membrane redox homeostasis on T cell membranes within the oxidative tumor microenvironment. Contrast-enhanced fluorescence imaging in the near-infrared II spectral region with a deep learning network is employed to visualize in vivo dynamics of the antibody conjugates. The antibody conjugates demonstrate enhanced and accelerated tumor accumulation, thereby promoting T cell proliferation and augmenting the antitumor efficacy. Mechanistic investigations reveal that the conjugate-mediated regulation of the T cell surface redox state protects against damage induced by extracellular reactive oxygen species, subsequently mitigating ferroptosis of T cells. In murine models, the antibody conjugates effectively suppressed colorectal tumor growth and recurrence, leading to a significant extension of animal survival. This work thus realizes reversing suppressive immune microenvironment from multiple dimensions with a simple checkpoint inhibitor conjugate, promising for clinical translation and next-generation immune checkpoint blockade therapy.