More than the sparse infiltration in glioblastoma, cytotoxic T lymphocytes (CTLs) also function inefficiently and overexpress the inhibitory markers, especially the identified NK cell receptor (NK1.1). However, most studies solely focus on how to augment tumor-infiltrating CTLs and overlook their killing maintenance. Metalloimmunotherapy has been proven to improve the functionalities of CTLs, but it has barely adapted to glioblastoma due to the severe limitations of safe delivery and the brain's physiological properties. Herein, we synthesized an amphipathic polyethylene glycol (PEG) polymer (designated as MPP) modified with the choline analogue 2-methacryloyloxyethyl phosphorylcholine (MPC) and polyphenol moieties to customize a nanoeditor (Mg2+@MK-8931@MPP) by coordinating Mg2+ and entrapping the hydrophobic BACE1 inhibitor MK-8931, then precisely redressing the gliomatous CTL sparsity and cytotoxic dysfunction. Upon MPC-assisted local accumulation in glioblastoma, Mg2+@MK-8931@MPP nanoeditors release MK-8931 to repolarize M2-like macrophages, facilitating CTL infiltration quantitatively. The cenogenetic immune adjuvant Mg2+ ulteriorly fortifies the T-cell receptor downstream signals to enhance the functionality of the ingoing CTLs in quality, leading to the secretion of high-level antitumor cytokines and cytotoxic proteins. Further blocking the inhibitory NK1.1 on CTLs by anti-NK1.1 antibodies can extend their cytolytic endgame. Studies on T-cell-deficient and wild-type mouse models support the immunomodulating feasibility of Mg2+@MK-8931@MPP. This gliomatous CTL-tailored strategy concurrently broadens metalloimmunotherapy to glioblastoma treatment and highlights the necessity of enforcing gliomatous CTLs' functionality.
Keywords: cytotoxic T lymphocytemodulation; glioblastoma; macrophage polarization; magnesium-phenolic coordination; metalloimmunotherapy.