Peptide-functionalized biomaterials as emerging platforms to enhance CAR-NK cell therapy in solid tumors

Chimeric antigen receptor natural killer (CAR-NK) cell therapy has emerged as a promising approach for cancer immunotherapy, offering potent antitumor activity together with the potential for allogeneic, off-the-shelf application. However, its efficacy in solid tumors remains limited by poor tumor trafficking and infiltration, insufficient persistence, physical extracellular matrix barriers, metabolic stress, and immunosuppressive signals within the tumor microenvironment (TME). Biomaterial-based delivery systems, particularly injectable hydrogels and engineered scaffolds, offer opportunities to improve the local retention, protection, and functional support of therapeutic immune cells. Peptide functionalization can further introduce defined biological cues that regulate cell–material interactions, tumor localization, matrix remodeling, and stimulus-responsive delivery. This review critically examines the emerging role of peptide-functionalized biomaterials in supporting CAR-NK cell therapy for solid tumors. We discuss key design parameters, including peptide density and spatial presentation, and compare ECM-derived adhesive peptides, tumor-targeting and tumor-penetrating peptides, immune-synapse-oriented strategies, and stimuli-responsive peptide systems. Particular attention is given to the distinction between direct evidence obtained in CAR-NK models and findings derived from conventional NK cells, CAR-T cells, or other biomaterial and drug-delivery systems. We further evaluate the potential of these platforms to improve tumor localization, cell retention, infiltration, metabolic support, and interactions with the TME, while considering off-target effects, tumor heterogeneity, manufacturing complexity, and translational challenges. Current evidence remains predominantly preclinical, and direct demonstrations of therapeutic benefit from peptide-functionalized biomaterials in CAR-NK systems are still limited. Future progress will therefore require CAR-NK-specific validation, quantitative characterization of peptide presentation, appropriate non-functionalized controls, and rational integration of peptide functionality with scalable biomaterial and cell-manufacturing strategies.