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The study reported by Gao Yanfeng, Si Xinghua, and Zhu Xueqin from the School of Pharmacy (Shenzhen), Sun Yat-sen University, directly addresses a bottleneck that has been repeatedly confirmed but still remains difficult to solve in current tumor immunotherapy: immune checkpoint blockade often simultaneously induces compensatory enhancement of myeloid immune suppression, especially the infiltration of neutrophils and inhibitory myeloid cells driven by the CXCL8-CXCR1/2 axis, thereby leading to the failure of anti-PD-1/PD-L1 therapy.
The authors, from the perspective of materials and molecular engineering, constructed a dual-specific peptide-nanomachine conjugate system (BsPNEC). This system simultaneously blocks PD-L1-mediated T cell exhaustion at the molecular level and CXCR1/2-mediated immunosuppressive myeloid cell recruitment at the material level; in the material aspect, Fe₃O₄ nanomachines are introduced to activate the cGAS-STING pathway through H₂O₂-dependent ROS production in the tumor microenvironment, thereby amplifying the innate immune signal and promoting CD8⁺ T cell infiltration.
From the perspective of biomaterials, this design is not a simple "targeting + immune activation" combination, but a clearly hierarchical immune reprogramming system:
The surface peptide is responsible for precise spatial positioning and unlocking of pathways, while the nanomachine is responsible for spatially limited immune amplification. The two work together to transform "cold tumors" into an immunologically active state with T cell enrichment. This strategy has been verified to have significant efficacy in an anti-PD-L1-resistant pancreatic cancer model, and it also has MRI imaging capabilities, demonstrating strong translational potential. The relevant research, titled "Design of a bispecific peptide-nanozyme conjugate for cancer immunotherapy", was published in Cell Reports Medicine.
Original link：https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00641-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS266637912500641X%3Fshowall%3Dtrue
