嵌合抗原受体T（CAR T）细胞免疫疗法在治疗许多癌症方面取得了成功。然而，它常常引发危及生命的细胞因子释放综合征（CRS）和神经毒性。在这里，我们展示了将聚乙二醇（PEG）原位共轭到CAR T细胞表面（'PEG化'）可以创建一个聚合物间隔体，阻止CAR T细胞、肿瘤细胞和单核细胞之间的细胞间相互作用。这种阻塞妨碍了CAR T细胞对肿瘤的强烈溶解和对单核细胞的激活，从而降低了有毒细胞因子的分泌，并缓解了与CRS相关的症状。随着时间的推移，CAR T细胞的缓慢扩增降低了PEG表面密度，并恢复了CAR T细胞-肿瘤细胞间的相互作用，诱导出强效的肿瘤杀伤作用。这种恢复发生在CAR T细胞-单核细胞相互作用恢复之前，为CAR T细胞在单核细胞过度激活之前提供了治疗时机。与治疗性抗体托珠单抗相比，治疗时致命的神经毒性也较低，证明原位PEG化CAR T细胞提供了一种基于材料的更安全的细胞免疫治疗策略。

Chimeric antigen receptor T (CAR T) cell immunotherapy is successful at treating many cancers. However, it often induces life-threatening cytokine release syndrome (CRS) and neurotoxicity. Here, we show that in situ conjugation of polyethylene glycol (PEG) to the surface of CAR T cells ('PEGylation') creates a polymeric spacer that blocks cell-to-cell interactions between CAR T cells, tumour cells and monocytes. Such blockage hinders intensive tumour lysing and monocyte activation by CAR T cells and, consequently, decreases the secretion of toxic cytokines and alleviates CRS-related symptoms. Over time, the slow expansion of CAR T cells decreases PEG surface density and restores CAR T cell-tumour-cell interactions to induce potent tumour killing. This occurs before the restoration of CAR T cell-monocyte interactions, opening a therapeutic window for tumour killing by CAR T cells before monocyte overactivation. Lethal neurotoxicity is also lower when compared with treatment with the therapeutic antibody tocilizumab, demonstrating that in situ PEGylation of CAR T cells provides a materials-based strategy for safer cellular immunotherapy.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.