PEG‐Sheddable Nanodrug Remodels Tumor Microenvironment to Promote Effector T Cell Infiltration and Revise Their Exhaustion for Breast Cancer Immunotherapy

Abstract Low infiltration of cytotoxic T lymphocytes and their exhaustion manifest the two concurrent main hurdles for achieving effective tumor immunotherapy of triple‐negative breast cancer. It is found that Galectin‐9 blockage can revise the exhaustion of effector T cells, meanwhile the repolarization of protumoral M2 tumor‐associated macrophages (TAMs) into tumoricidal M1‐like ones can recruit effector T cells infiltrating into tumor to boost immune responses. Herein, a sheddable PEG‐decorated and M2‐TAMs targeted nanodrug incorporating Signal Transducer and Activator of Transcription 6 inhibitor (AS) and anti‐Galectin‐9 antibody (aG‐9) is prepared. The nanodrug responds to acidic tumor microenvironment (TME) with the shedding of PEG corona and the release of aG‐9, exerting local blockade of PD‐1/Galectin‐9/TIM‐3 interaction to augment effector T cells via exhaustion reversing. Synchronously, targeted repolarization of M2‐TAMs into M1 phenotype by AS‐loaded nanodrug is achieved, which promotes tumor infiltration of effector T cells and thus synergizes with aG‐9 blockade to boost the therapeutic efficacy. Besides, the PEG‐sheddable approach endows nanodrug with stealth ability to reduce immune‐related adverse effects caused by AS and aG‐9. This PEG sheddable nanodrug holds the potential to reverse the immunosuppressive TME and increase effector T cell infiltration, which dramatically enhances immunotherapy in highly malignant breast cancer.