Expanding the ACT paradigm: B cell engineering via spherical nucleic acids for cancer immunotherapy

Adoptive cellular therapy (ACT) has revolutionized cancer immunotherapy, yet its focus remains largely on T cells. B cells, despite their potent antigen-presenting capacity and role in adaptive immunity, have been underutilized due to inefficient antigen delivery and activation. We developed an ex vivo strategy leveraging spherical nucleic acids (SNAs) to license B cells for ACT. This platform synchronizes pH-controlled co-delivery of tumor antigen peptides and TLR9 agonists into shared endosomal compartments, enabling sustained antigen presentation and robust cross-priming of tumor-specific CD8⁺ T cells, resulting in epitope spreading and durable antitumor immunity.SNA-trained B cells exhibited lymphoid homing and secreted CCL3/CCL4, establishing a CCR5-dependent chemotactic axis that recruited effector CD8⁺ T cells and cDC1, creating spatial immune hubs within tumors. Multiplex immunohistochemistry analysis revealed clustering of transferred B cells, CD8⁺ T cells, and cDC1 in draining lymph nodes, facilitating antigen handoff and reciprocal activation. Mechanistic studies confirmed that CCR5 blockade or CD8⁺ T-cell depletion abrogated efficacy. Across multiple murine and humanized tumor models, SNA-trained B cells outperformed controls, reduced metastasis, and synergized with PD-1 blockade to improve survival. Single-cell transcriptomics and BCR-seq demonstrated progression toward plasma cell differentiation, oligoclonal expansion, and IgG2 class switching.This work introduces a nanomaterial-based platform to reprogram B cells for ACT, overcoming limitations in immunologically “cold” and checkpoint-refractory tumors. SNA-trained B cells broaden the ACT paradigm beyond T cells, offering a versatile and well-tolerated strategy for durable antitumor immunity.