Advanced breast cancer immunotherapy: Surface modification of NK cells for embedding antibody-drug conjugates

Abstract

The combination of antibody-drug conjugates (ADCs) and immunotherapy has emerged as a promising strategy for cancer treatment. However, effective integration of chemotherapy and immunotherapy remains a challenge. Here, we introduce a universal surface-engineered NK (USE-NK) platform, which rapidly modifies immune cells into a targeted chemoimmunotherapy system by enabling the spontaneous incorporation of antibodies or ADCs. This platform utilizes a recombinant fusion protein (C3) derived from Protein G and a polymeric lipid-based conjugation strategy to stably attach therapeutic antibodies to NK cell surfaces without genetic modifications, preserving their native functionality. This approach enhances tumor targeting, minimizes off-target toxicity, and maintains NK cell cytotoxicity. Both in vitro and in vivo studies demonstrated that USE-NK conjugated with trastuzumab (TZ) or trastuzumab-emtansine (T-DM1) exhibited superior HER2-positive cancer cell recognition and cytotoxicity compared to NK cells treated with each agent separately. This enhancement was driven by the combined effects of 1) targeted delivery of potent chemotherapeutic agents with minimizing off-target toxicity, 2) enhanced mobilization of USE-NK toward tumor tissue, and 3) the cytotoxic activity of USE-NK against cancer cells. This rapid, non-invasive, and reversible engineering method provides a flexible approach to chemoimmunotherapy. Additionally, it extends beyond NK cells to other immune cell therapies, including CAR-T and CAR-NK cells. By leveraging the antibody-binding ability of C3, this platform enables multi-antigen targeting to address tumor heterogeneity. The scalability and adaptability of USE-NK position it as a promising candidate for personalized and off-the-shelf cancer immunotherapies.