Engineered stem cell-derived CD16-enhanced universal NKT cells improve monoclonal antibody-based cancer immunotherapy

Monoclonal antibody (mAb)-based therapies have revolutionized cancer treatment; however, their clinical efficacy is often limited by insufficient antibody-dependent cellular cytotoxicity (ADCC), tumor antigen escape, and an immunosuppressive tumor microenvironment (TME). To overcome these limitations, we developed an allogeneic stem cell-derived invariant natural killer T (NKT) cell platform engineered to express a high-affinity non-cleavable CD16 receptor (CD16HSC-NKT) for broad enhancement of mAb-based immunotherapy. Using a clinically guided differentiation platform, we generated highly pure and scalable CD16HSC-NKT cells exhibiting robust expression of NK receptors, potent cytotoxic machinery, and a Th1-biased cytokine profile. CD16HSC-NKT cells demonstrated potent intrinsic antitumor activity and potently enhanced the efficacy of multiple therapeutic antibodies, including Trastuzumab, Tafasitamab, Rituximab, Daratumumab, and Cusatuzumab, across diverse hematologic and solid tumor models. In vivo, combination therapy induced durable tumor eradication and prolonged survival in xenograft models, outperforming the clinically approved antibody-drug conjugate trastuzumab deruxtecan. Mechanistically, therapeutic antibodies promoted the expansion, persistence, and activation of CD16HSC-NKT cells within tumors. CD16HSC-NKT uniquely remodeled the TME by selectively depleting CD1d-expressing tumor-associated macrophages and myeloid-derived suppressor cells. CD16HSC-NKT cells also exhibited minimal alloreactivity, no graft-versus-host disease, and no detectable systemic toxicity. Collectively, these findings establish CD16HSC-NKT cells as a safe, off-the-shelf cellular platform capable of broadly enhancing monoclonal antibody therapy through sustained ADCC, multimodal tumor targeting, and TME remodeling.