A universal multi-receptor NK cell platform engineered for synergistic combination with antibody and T-cell engager therapies

Background: Monoclonal antibodies (mAbs) and T-cell engagers (TCEs) redirect immune effector cells toward malignant targets, yet their efficacy is often limited by patient T- and NK-cell dysfunction. Conventional CAR strategies target a single antigen, requiring new construct design, GMP production, and separate regulatory pathways for each target. To combine the strengths of engager- and cell-based approaches, we developed PluraliNK cells, a universal multireceptor NK-cell platform activated through CD3/TCR- and Fc-dependent pathways. This enables redirection by any approved mAb or TCE without additional engineering, creating a flexible plug-and-play NK therapy. Methods: NK cells were engineered using two polycistronic vectors to express the full CD3 complex, IL-15 for cytokine support, high-affinity CD16A (F158V) for enhanced Fc engagement, and an invariant TCR alpha/beta (iTCR) to stabilize CD3 and permit CD1d-restricted recognition. This dual-activation system allows PluraliNK cells to respond to CD3- or CD16-mediated signals and to pair with diverse mAbs or TCEs without further modification. Results: PluraliNK cells showed potent cytotoxicity across hematologic and solid tumor models when combined with approved mAbs (rituximab, trastuzumab) or TCEs (blinatumomab, glofitamab, elranatamab), consistently outperforming mAb/TCE monotherapy or unmodified NK cells. The platform supports simultaneous engagement by multiple antibodies or TCEs, enabling clearance of heterogeneous tumor populations and reducing antigen escape. Dual-input signaling enhanced activation, serial killing, and resistance to exhaustion, an advantage in solid tumors with spatial heterogeneity and lineage plasticity. Because PluraliNK activation depends on an external mAb or TCE, the system provides an additional safety layer compared with constitutively active CAR constructs. In NSG xenograft models, PluraliNK cells combined with mAbs or TCEs achieved superior tumor clearance, improved infiltration, and enhanced in vivo persistence without off-target toxicity. Conclusions: This universal NK-cell platform enables multiantigen targeting and integration with existing mAbs and TCEs, addressing tumor heterogeneity and immune escape without requiring antigen-specific CAR redesign. A first-in-human clinical trial of PluraliNK cells with antibody therapy has been initiated.