Supramolecular polyrotaxane-based nano-theranostics enable cancer-cell stiffening for enhanced T-cell-mediated anticancer immunotherapy
Haifen Luo, Jingqi Lv, Peiye Wen, Shan Zhang, Wen Ma, Zhèn Yáng
Abstract
Despite the tremendous therapeutic promise of activating stimulators of interferon genes (STING) enable to prime robust de novo T-cell responses, biomechanics-mediated immune inhibitory pathways hinder the cytotoxicity of T cells against tumor cells. Blocking cancer cell biomechanics-mediated evasion provides a feasible strategy for augmenting STING activation-mediated anti-tumor therapeutic efficacy. Here, we fabricate a redox-responsive Methyl-β-cyclodextrin (MeβCD)-based supramolecular polyrotaxanes (MSPs), where the amphiphilic diselenide-bridged axle polymer loads MeβCD by the host-guest interaction and end-caping with two near-infrared (NIR) fluorescence probes IR783. The MSPs self-assemble with STING agonists diABZIs into nanoparticles (RDPNs@diABZIs), which enable simultaneous release of MeβCD and diABZIs in the redox tumor microenvironment. After the released diABZIs activate STING on antigen-presenting cells (APCs), de novo T-cell responses are initiated. Meanwhile, the released MeβCD depletes membrane cholesterol to overcome cancer-cell mechanical softness, which enhances the CTL-mediated killing of cancer cells. In the female tumor-bearing mouse model, we demonstrate that RDPNs@diABZIs lead to effective tumor regression and generate long-term immunological memory. Furthermore, RDPNs@diABZIs can achieve significant tumor eradication, with these mice remaining survival for at least 2 months. Activation of stimulator of interferon genes is promising for initiating robust de novo T-cell responses, but biomechanics-mediated immune inhibitory pathways hinder the cytotoxicity of T cells against tumor cells. Here, the authors report redox-responsive supramolecular polyrotaxanes nanoformulations that augment anti-tumor T-cell killing by overcoming cancer-cell mechanical softness.