Tumor Necrosis Factor (TNF) ligands are trimeric cytokines with therapeutic potential, but their soluble forms often lack sufficient receptor clustering for potent activity, while stronger agonists risk systemic toxicity. We combine trimer interface editing with ligand-gated clustering to engineer multi-specific TNF ligand fusions designed for tumor-conditional higher-order receptor assembly. Across several TNF ligands, we link biophysical properties and receptor engagement to cellular activity and in vivo antitumor efficacy.

T cells can be redirected to recognize HLA/peptide antigens via engineered TCRs or TCR-mimetic CARs, but differences in antigen recognition and signaling may shape the relative effectiveness of these therapies. Preclinical comparisons between these platforms highlight a balance between sensitivity and durable anti-tumor activity. The findings demonstrate how provision of additional signaling, through either engineering or combination therapies, can improve T-cell expansion/fitness, informing strategies to develop more effective cell therapies.

• Fapon Biopharma’s modular VHH T cell engager platform features a human–cynomolgus cross-reactive CD3-TCR nanobody with conditional activation, minimal off-target binding, and favorable developability. Three differentiated programs demonstrate its versatility: 
• FP014 targets CD19/BCMA for B-cell and plasma-cell depletion; FPE021 pairs CDH17 targeting with CD28 co-stimulation for gastrointestinal cancers; and FPE026 enables preferential CD8+ T cell engagement. 
• Flexible target combinations and molecular formats support development across oncology and autoimmune diseases with distinct therapeutic needs.